\r\n\tAn update on clinical manifestations, their assessment, monitoring, and imagiology, including peripheral arthritis, enthesopathy, and extra-articular findings, and, the differential diagnosis with other diseases which evolves with axial and peripheral calcifications will be provided.
\r\n
\r\n\t \r\n\tAn important component of this book must be dedicated to the more recent treatments namely with biologic therapies but focusing also on new small molecule inhibitors and experimental therapies.
",isbn:"978-1-80356-267-4",printIsbn:"978-1-80356-266-7",pdfIsbn:"978-1-80356-268-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d13ec1a1832b3d86803555ea2d5f9759",bookSignature:"Dr. Serdar Küçük",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11455.jpg",keywords:"Robot Manipulator, Serial Manipulator, Parallel Manipulator, Hybrid Manipulator, Kinematics, Dynamics, Simulation Tool, Structural Design, Robotic Technology, Robotic Structure, Optimization, Control",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 10th 2022",dateEndSecondStepPublish:"April 14th 2022",dateEndThirdStepPublish:"June 13th 2022",dateEndFourthStepPublish:"September 1st 2022",dateEndFifthStepPublish:"October 31st 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Serdar Küçük does research in kinematics and dynamics of serial and parallel robotic manipulators, as well as in the design of electrically controlled, above-knee prosthetics and hand–wrist rehabilitation robots, surgical robots, and biomedical robotic devices.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"5424",title:"Dr.",name:"Serdar",middleName:null,surname:"Küçük",slug:"serdar-kucuk",fullName:"Serdar Küçük",profilePictureURL:"https://mts.intechopen.com/storage/users/5424/images/system/5424.jpeg",biography:"Serdar Küçük received a BA and MSc from Marmara University, Istanbul, Turkey, in 1995 and 1998, respectively. 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\n
1. Introduction
\n
No matter chemical fertilizers or manures, using fertilizers for the purpose of improving the fertility of the soil and the productivity of the crops have caused that the biogeochemical cycles in the nature have been affected negatively [1, 2], and the nutrients (specifically nitrogen (N) and phosphorus (P) were run off, which ultimately caused degradation in the environment [3, 4]. There are several underlying reasons for this situation some of which are the low use-effectiveness of fertilizers and the constant long-term use. Although there are damaging environmental effects, it is expected that the total fertilizer amounts that are used in the whole world will increase in future due to the ever-increasing world population, because there appears a need for producing more food by applying intensive agriculture, which necessitates a great amount of fertilizers [5, 6].
\n
There are two objectives in modern horticulture that contradict with each other: the need to provide food for ever-rising population of the world; and the need for minimizing the damage done to the environment, which can affect horticulture in a negative way [7]. In this respect, horticultural industry and scientists face a major sustainability challenge [8]. In the past 10 years time period, there were some innovations in the field of technology to improve the sustainability of the production systems by reducing the use of chemicals. “Biostimulants” have been proposed as an effective tool in this context. As a result of the efforts made to reduce the harmful effects of fertilizers, plant growth promoting rhizobacteria (PGPR) and/or arbuscular mycorrhizae fungi (AMF) have been proposed as complements for fertilizers. “Plant biostimulants contain substance(s) and/or microorganisms whose function when applied to plants or to rhizosphere is to stimulate natural processes to enhance nutrient uptake, effectiveness, tolerance to abiotic stress, and crop quality, with no direct action on pests.”
\n
The rhizosphere is a soil volume under the effect of plant roots. Hiltner [9] defined “rhizosphere” as a maximum microbial activity zone. The microbial population that exists in this medium is different from the population that surrounds it because of the root exudates, which act as nutrition source for microbial growth [10]. The microorganisms may exist in the rhizosphere, rhizoplane, root tissue, and/or in a specialized root structure that is named “nodule.” Among the plant, soil, and microorganisms that exist in the soil medium, significant interactions were reported [11]. These significant interactions can be beneficial, neutral, and/or harmful, and may affect growth of plants [12, 13, 14]. Usually there are bacteria, algae, fungi, protozoa, and actinomycetes in the microorganisms that colonize in the roots of plants. Evidence has been presented about the enhancement of plant growth and development by applying these microbial populations [15, 16, 17, 18, 19]. Bacterial population, i.e., fungi include a significant portion of soil rhizosphere microflora and affect plant growth. The togetherness of fungi and plant roots (mycorrhizae), which is symbiotic life, enhances the root surface area, and this enables the plant to absorb water and nutrients from big soil volume in a more efficient manner. Two mycorrhizae (ecto- and endo-mycorrhizae) types were reported in a few plant species. The mycorrhizae increase the availability of the nutrients and water, and in addition, protect the plant from some abiotic stresses [20, 21].
\n
Agriculture is influenced greatly by the climate change; especially agriculture in tropical areas face increased stress because of natural and anthropogenic factors. In some major crops, increased abiotic and biotic stress is a major cause for productivity stagnation. It has been considered as a big difficulty to develop efficacious, low-cost, and easy-to-apply methods in abiotic stress management. Many studies have been conducted throughout the world for the purpose of developing tactics to deal with abiotic stress. In such studies, developing species that are tolerant to heat and drought, changing crop cultivation times, resource management, etc., were applied [22]. Many newly introduced technologies are cost-effective. Some studies conducted recently have reported that microorganisms could help crops fight against abiotic stress. It has long been recognized that microorganisms have effects on plant growth, nutrient management, and disease control. Some useful microorganisms invade the rhizosphere/endorhizosphere of plants. They enhance plants via some direct-indirect mechanisms [23]. In addition to these, the role of microbes in biotic and abiotic stress management has been focused on more in recent times. Soil supports plant growth through complex and dynamic systems. Plant growth and development are affected by some stresses which are major constraints for sustainable agricultural production in the soil environment. Biotic stresses include plant pathogens and pests (viruses, bacteria, fungi, insects, and nematodes). Abiotic stresses are salinity, drought, flooding, heavy metals, temperature, gases, and deficiency of nutrients or excessive nutrients. Abiotic stresses cause yield reduction, and their intensity changes according to the soil types and plant factors. Imbalance in hormones and nutritive elements, physiological disorders (epinasty, abscission, and senescence), and susceptibleness to diseases are some of the general impacts of these stresses [24, 25, 26, 27, 28].
\n
\n
\n
2. Beneficial microorganisms against stress conditions PGPR and mycorrhiza
\n
\n
2.1. Plant growth promoting rhizobacteria (PGPR)
\n
Plant growth promoting rhizobacteria (PGPR) are useful bacteria that act on some soil types and facilitate that plants grow and develop in (in)direct ways. In a direct way, fixed nitrogen, phytohormones, iron isolated by bacterial siderophores, i.e., iron-carriers, and phosphate in soluble form are given to plants. In an indirect way, phytopathogens (biocontrol) are avoided resulting in plant growth enhancement. Such functions are performed by PGPR through several enzymes (like bacterial 1-aminocyclopropane-1-carboxylate (ACC) deaminase) stimulating physiological changes at molecular level. ACC has an important effect on ethylene regulation, which is a plant hormone, resulting in modified plant growth and development. Bacterial strains with ACC deaminase may eliminate negative effects caused by stress and mediated by ethylene.
\n
It was reported that there was ACC deaminase in some Gram-negative microbial bacteria, Gram-positive bacteria, rhizobia, endophytes, and fungi. It was investigated in some species of plant growth enhancing bacteria (Agrobacterium genomovars and Azospirillum lipoferum, Alcaligenes and Bacillus, Burkholderia, Enterobacter, Methylobacterium fujisawaense, Pseudomonas, Ralstonia solanacearum, Rhizobium, Rhodococcus, and Sinorhizobium meliloti, and Variovorax paradoxus).
\n
The ACC of the root is metabolized into α-ketobutyrate and ammonia by the ACC deaminase. It also checks the ethylene production. If this process did not occur in this way, the growth of the plant would be inhibited via some mechanisms. If plants are treated with bacteria that have ACC deaminase, it is possible that they have extensive root growth because of less amounts of ethylene. In this way, plants may resist several stress sources. In recent years, using PGPR with ACC deaminase activity, to improve the growth of plants under stress and normal conditions, has been dealt with researchers as an interesting and new field. Also, cultivars’ genetic manipulation with genes that express this enzyme has been dealt with recently by several authors. For this reason, focus must be laid on the further parts of this manuscript on late developments in this field of biotechnology.
\n
Data on biosynthetic pathways of ethylene production in plants enabled us to elucidate the mechanisms by which plants regulate the endogenous ethylene level for their normal growth. It has been demonstrated that S-adenosylmethionine or ACC-degrading enzymes decrease ethylene levels in an efficient manner without changing plant physiology. For this purpose, researchers investigated some enzymes that aid to decrease ethylene levels in plants. In this respect, S-adenosylmethionine (SAM) hydrolase and SAM decarboxylase were examined less with regards to ethylene regulation in plants. ACC synthase and oxidase were examined more with several plants.
\n
The ACC deaminase, which is a pyridoxal 5-phosphate (PLP)-dependent polymeric enzyme, was first investigated in a soil bacteria species Pseudomonas sp. strain. Bashan et al. [29] described structure for ACC deaminase and provided an understanding about the working of sole pyridoxal-5-phosphate that depends on cyclopropane ring-opening reactions of this enzyme in Pseudomonas sp. It was reported in [30] that there was a wide range (>100-fold) in ACC deaminase activity level in various organisms which show high ACC deaminase activity and typically bind to some plants. In this group, there are rhizosphere, phyllosphere organisms, and endophytes, which may behave as a sink-like structure for ACC that appear as a result of stress in plants. In addition, the abovementioned show little preference for one plant over another. However, the organisms that express low deaminase may only bind to some plants. They may also be expressed solely in some tissues; and do not reduce the level of ethylene in plants; but, they prevent a localized increase in the levels of ethylene. Glick reported that there are some rhizobia and ACC deaminases.
\n
Glick et al. [31] investigated the model of PGPR which includes ACC deaminase. They examined how a bacterial ACC deaminase with a low relation to ACC could cope with plant enzymes and ACC oxidase that has high relation with the same substrate resulting in a reduction of endogenous ethylene concentration of a plant. They claimed that biological activity of PGPR was related with ACC deaminase ACC oxidase amounts. In order for PGPR to decrease ethylene levels in plants, the level of the ACC deaminase must be minimum from 100- to 1000-fold bigger than ACC oxidase level. For this to happen, the ACC oxidase expression must not be induced.
\n
Indole-3-acetic acid (IAA) is synthesized and excreted by PGPR. IAA is adsorbed by the surface or roots of the seeds of plants by tryptophan and some molecules in seeds or root exudates. Plants take up some IAAs that are synthesized recently, and IAAs may stimulate the cell proliferation and elongation of plants. In addition, SAM is converted into ACC by enzyme ACC synthetase stimulated by IAA. In the model of Glick et al., an important deal of ACC can be exuded from the roots or seeds of plants. It may also be taken up by soil microbes. It is also possible that it is hydrolyzed by vital microbial enzyme ACC deaminase to produce ammonia and α-ketobutyrate. This process causes that the ACC amount is reduced outside plants. In addition, the balance between internal-external ACC is kept stable via the exudation of more ACC into the rhizosphere. Soil microbial communities with ACC deaminase activity cause that plants biosynthesize more ACC than the plant could need and arouse ACC exudation from plant roots. Meanwhile, they will also provide microorganisms with nitrogen (ACC). As a result, microorganism with ACC deaminase growth is enhanced near roots of the plants. In this way, the ACC level is reduced in plants, and also, the ethylene (stress hormone) biosynthesis is inhibited. In some studies, PGPR inoculation with ACC deaminase was shown to change the endogenous ethylene levels, which ultimately lead to variations in plant growth.
\n
Several chemicals (aminoethoxyvinylglycine (AVG), aminooxyacetic acid (AOA), and 1-methylcyclopropene (1-MCP)) were used to reduce the ethylene level in plants. They were also used to change the sensitivity to ethylene during fruit ripening and flower wilting. In many situations, these chemical substances are not cheap, not easily obtained, and are harmful for the environment. Using PGPR in a natural soil and plant environment is more economical and feasible and is more economical friendly because PGPR includes ACC deaminase activity. In addition, it has also some other advantages like the ACC deaminase trait being more common in some PGPR species that are native to rhizosphere and have a wide variety of survival potential in rhizosphere and rhizoplane. Moreover, PGPR has some other aspects (such as auxins, gibberellins, cytokines, and/or polyamines syntheses contributing directly to plant growth). These features cause that the selection of PGPR with ACC deaminase is more reliable than other alternatives.
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\n
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2.2. Mycorrhizae
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AMF were first described in the last years of nineteenth century. Albert Bernard Frank described the symbiotic associations between the plant roots and the fungi (mycorrhizae). Mycorrhizae means “fungal root.” This association’s basic principle is the nutrients taken up from the soil are exchanged with sugar. Lots of microorganisms form symbiosis with plants ranging on a continuous scale from parasitic to mutualistic. A typical example of these widespread mutualistic symbioses is the arbuscular mycorrhiza formed between AMF and vascular flowering plants [32]. Many scientists and mycologists researched the relations (associations) between mycorrhizae and the plants biology and their inoculation methods. This relation includes the structure of the root and mycorrhizal inoculation. Mycorrhizae are complex symbioses and the fungi produce some structures in the root. Quantification of the structures (hyphae, arbuscules, and vesicles) was standardized by the method suggested by Hungria and Vargas [33]. An arbuscular mycorrhiza has three important elements; the root, the fungal elements between the cells of the root and an extraradical mycelium in soil [34]. The most common type of mycorrhizae is the arbuscular mycorrhiza occurring in about 90% of plant species infected with mycorrhiza. The most common type of mycorrhizae is the arbuscular mycorrhiza occurring in about 90% of plant species infected with mycorrhiza, approximately 83% of dicotyledons, 79% of monocot, and 100% of gymosperms. Most crop plants form mycorrhizae with the exception of the Brassicaceae (e.g., mustard, cabbage, and canola) and Chenopodiaceae (e.g., sugar beets and spinach).
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AM fungi consists approximately 160 species belonging to three families. Glomaceae, Gigasporaceae, and Acaulosporaceae. More than 6000 fungal species can form mycorrhizae with about 240,000 plant species. AMF plants own bigger extraradical hyphae formation and soil aggregation. They enhance tilth and excrete hydrophobic protein called “glomalin.” AMF produce more stress-resistant plants during production and for landscape, they reduce the pesticide usage, they increase the more drought and nutrient tolerant plants in landscape, and they potentially higher transplanting success and faster establishment. A symbiotic association formed by fungi with roots, exchanging for functioning as an extended root system, the fungi receives carbonhydrates from the host plant [35].
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Arbuscular mycorrhizae fungi (AMF), which are useful organisms, have a significant role in performance and nutrition with plant mineral intake capacity [36]. AMF symbiosis is especially significant in improving the immobile uptake and indissoluble phosphate ions in soil with the interactions with bi/trivalent cations (especially Ca2+, Fe3+, and Al3+ [37, 38]. The main function in this mutualism is the capacity of AMF in developing external hyphae networks that may extend the surface area (up to 40 times) and the explorable soil volume for nutrient intake [39] by producing enzymes and/or excreting organic substances [40]. AMF can excrete phosphatases to hydrolyze phosphate from organic P-compounds [41, 42, 43], which enhance productivity under harsh conditions (deficiency of phosphorus; [44]). The extraradical hyphae are considered significant in terms of intake of ammonium, immobile micronutrients (Cu and Zn), and some mineral cations coming from the soil (K+, Ca2+, Mg2+, and Fe 3+) [45, 46]. It was demonstrated that AMF enhance plant nutrition (biofertilizers), and interferes with the phytohormone balance of the plants, which in turn affects development of plant (bioregulators) and alleviates the influence of the environmental stresses (bioprotectors). This increases the biomass and yield, and causes shifts in some quality parameters [47].
\n
The horticultural products have high phytochemical elements (carotenoids, flavonoids, and polyphenols) and therefore meet the desires of consumers and authors with their health/benefit influences [48]. Furthermore, AMF also bring tolerance to drought [49, 50] and salinity [51, 52], nutrient deficiency, heavy metal contamination [53] and in adverse soil pH [54, 55].
\n
The AMF life cycle begins with asymbiotic stage (germination of the asexual chlamydospores). This depends on several physical factors (temperature and humidity). AMF retract the cytoplasm without the presence of a plant and turn to the dormant phase because they are obligate biotrophs. However, near the roots of the plants, the presymbiotic phase begins with the ramification of the primary germ tube [56]. Root exudates [57] and specific metabolites (strigolactones) may also induce this [58]. When there is a physical contact with the surface of the root, the fungi build up hyphopodia (appressoria) on the surface. On the other hand, a particular mycorrhizae-specific process occurs in epidermal cells underlying hyphopodia in the plant side. They constitute the pre-penetration apparatus, which is a transient intracellular structure used by the fungi to enter the root [59]. Fungal hyphae host the roots of the plant, firstly, between/through cells with linear/simple-coiled hyphae [60], and then build up high-branch hyphal structures that resemble a tree in plant cell apoplast (the arbuscules which gave the name). Gramineae members form vesicles rich in lipid as storage organs [61]. Parallel to the colonization of the root, fungi examines the soil around with its hyphae with which they uptake nutrients, interact with other microorganisms, and colonize roots of nearby plants of the same (or different) species. In this way, plants and their AM fungi are interrelated with each other in a network of roots and hyphae [62, 63]. They can exchange nutrients [64] or signals [65] in this way. Eventually, new chlamydospores are created in the extraradicular mycelium. The cycle of life is ended in this way.
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3. The most effective environmental stress factors: salinity and drought
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3.1. Salinity stress
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Under saline conditions, the changes in soil-water potential cause that plant water intake is reduced as well as the nutritional and hormonal imbalance. In these conditions, proline, glycine betaine, trehalose, polyols, and similar organic solutes accumulate in the body of the plant to preserve the plant from the stress-induced effects with osmotic adjustment, with limiting water loss and diluting the toxic ion concentration [66, 68]. Such an accumulation makes it possible for the plant to maintain osmotic potential for improved water intake. For instance, proline accumulation preserves the plant by adjusting osmotic pressure and by stabilizing many functional units (e.g., complex II of the electron transport system, proteins, and enzymes [69, 70]. There are two mechanisms in which high-concentration soluble salts influence microbes: osmotic effect and specific ion effect. Osmotic potential (more negative) is increased by soluble salts and draws water out of the cells, which in turn, may kill microbes and roots via plasmolysis. Because of the low osmotic potential, it becomes more difficult for roots and microbes to eliminate water from the soil [71]. Plants, as well as microbes, can adapt to low osmotic potential through accumulating osmolytes. However, osmolyte synthesis necessitates large amounts of energy, which in turn, results in reduced growth and activity [72, 73]. Certain ions, including Na+, Cl−, and HCO−3, are toxic for some plants when they are at high-concentrations [74]. In some previous studies, it was reported that salinity decreases microbial activity and microbial biomass and changes the structure of the microbial community [75, 76, 77, 78, 79]. The microbial biomass is decreased by salinity. The reason for this is that osmotic stress causes drying and cell lysis [80, 81, 82, 83, 84, 85, 86]. In previous studies, it was also reported that soil respiration was reduced with the increase in the soil EC [87, 88, 89]. Gerhardson [90] reported that soil respiration was decreased by more than 50% at EC1:5Z5.0 dS m1. However, according to Glick [91], soil respiration was not correlated at a statistically significant level with EC. However, they also reported that as EC increased, the metabolic quotient (respiration per unit biomass) also increased.
\n
Microorganisms can adapt to/tolerate stress salinity stress by accumulating osmolytes [91, 92, 93, 94, 95]. Among the main organic osmolytes, there are proline and glycine betaine; and among the common inorganic solutes, there are potassium cations, which are used as osmolytes accumulated by saline-tolerant microbes [96]. However, high amount of energy is necessary for the synthesis of organic osmolytes [97, 98]. Inorganic salts accumulation (as osmolytes) may be toxic, and for this reason, it is limited to halophytic microbes which developed saline-tolerant enzymes to survive in highly saline medium. Fungi have a tendency for being more sensitive to salt stress than bacteria [99, 100, 101, 102]. In this respect, the rate of bacteria/fungi may be increased in saline soils. When compared to nonsaline soils, salinity-tolerance differences among microbes cause those changes that appear in the structure of the community [103, 104].
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3.1.1. PGPR help plants tolerate salinity stress
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Salt stress enhances endogenous ethylene production in plants and mostly serves as a stress hormone. Probably decreasing the ethylene induced by salinity via any mechanism might reduce the negative effect of salt on the growth of plants. According to recent studies, plants inoculated with PGPR with ACC deaminase could cope with salinity stress with a normal growth pattern. According to Mayak et al. [105], Achromobacter piechaudii, which had ACC deaminase activity, increased fresh-dry weight of tomato seedlings at a great deal when grown in with NaCl salt (up to 172 mM). These bacteria decreased the ethylene production in tomato seedlings, and this situation would be stimulated if the seedlings were subjected to increased saline conditions. On the other hand, the sodium level in the plant could not be reduced, and phosphorus and potassium intake was increased. This situation may have enhanced the activation of the events that helped the relief of the side effects of the salt on the growth of the plants. In addition, these bacteria increased the water-use efficiency (WUE) under saline conditions. They also aided in relieving salt suppression of photosynthesis. According to Saravanakumar and Samiyappan [106], Pseudomonas fluorescens strain TDK1 that had ACC deaminase activity increased saline resistance of the groundnut plants. The strain also increased the yield when compared with Pseudomonas strain inoculation that lacked ACC deaminase activity. Glick et al. [107] verified that ACC deaminase bacteria provided plants with salt tolerance because they lower the salt-induced stress ethylene synthesis and enhance canola growth under saline conditions. We also saw similar results in maize under saline stress as a reaction to the inoculation with ACC deaminase PGPR. The results of research on the physiological effects of some vegetable species related to the benefits of PGPR in salt stress conditions are presented in Table 1.
Root length was observed better in the cuttings were treated with BA7, A16 and M3 compared to the other treatments. Mint cuttings inoculated with M3 had more dry matter content than control and the other treatments.
637 C and N 17/3 in bacteria have demonstrated positive results in practice. Both increased yield, nutrient element uptake and stem diameter.
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Table 1.
Summary of reported physiologic effects of plant growth promoting rhizobacteria (PGPR) under salinity stress conditions on different vegetables.
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3.1.2. Inducing salinity stress tolerance through inoculation of mycorrhizae
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The symbiosis of AM has increased the resilience of the host plants to saline stress, maybe with bigger consistency than to drought stress. Compared to uninoculated controls, growth in saline soils was increased by the inoculation with Glomus spp., and with AM plants that had increased phosphate and decreased Na+ concentrations in shoots [112, 113]. AM colonization in maize enhanced the salt resistance [114], and in mung bean [115] and in clover [116]. The AM influence had a correlation with enhanced osmoregulation/accumulation of proline. The inoculation of AM also enhanced NaCl resistance in tomato with extent of enhancement regarding the saline sensitivity of the cultivar [117]. AM enhancement of saline resistance was generally related with AM-related increase in P acquisition and plant growth in cucumber [118]. Gigaspora margarita colonization enhanced stomatal conductance in sorghum in drought stress in saline soils and also improved the survival dual-stress rates. Evelin et al. [19] investigated whether tomato (“Zhongzha” 105) with F. mosseae could increase its salt tolerance. They reported that mycorrhization facilitated salt-related reduction of growth and fruit yield, and also determined that the P and K concentrations were higher and Na concentration was lower in AMF in non-AMF tomato in 0, 50, and 100 mM NaCl. They also claimed that an improvement of the ROS-scavenging enzymes (such as superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX)) in leaves of salt-affected and control treatment accompanied AMF colonization.
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Compared to non-mycorrhizae plants, the bigger antioxidant enzyme activity in plants inoculated with AMF was related with the lower lipid peroxidation accumulation, which indicates lower oxidative harm in the mycorrhized plants. In a similar manner, Habibzadeh et al. [119] reported that enhancement in tolerance to saline stress (“Behta” and “Piazar”) of the tomato inoculated with R. intraradices was associated with a higher P, K, and Ca intake and with lower Na toxicity. The net photosynthesis enhanced mycorrhization through increasing stomatal conductance and protecting PSII [120]. It was claimed that the increased sink strength of AMF roots was the reason for the mycorrhizae promotion of stomatal conductance [121]. Furthermore, in [122], it was reported that the P, Cu, Fe and Zn accumulation was high in inoculated (F. mosseae) than in non-inoculated tomato plants in control and medium salinity groups. However, the Na concentration in the shoot was low in mycorrhized plants, which confirms that the tolerance of the plant to salt stress is enhanced by AMF colonization. Authors [123, 124, 125] reported that mycorrhizae pepper (“11B 14” and “California Wonder 300”), inoculated with Rhizophagus clarum and R. intraradices, had bigger biomass in shoots at different saline concentrations when compared to non-inoculated plants. In non-mycorrhizae plants, the lowest crop performance was reported to be associated with higher Na and lower N, P, K concentrations in leaf tissue and also with high leaf electrolyte leakage, but the effect of the saline stress on pepper shoot biomass varies among different fungi species at a significant level [126]. Cheng et al. [127] reported that inoculation with AMF (R. intraradices) might help to beat saline stress in zucchini-squash (Cucurbita pepo L. “Tempra”), which is a significant greenhouse vegetable. Enhanced nutrition (higher K and lower Na concentrations in leaf tissue) and the leaf water status might have helped plants to translocate minerals and assimilate to the sink, and alleviate the effects of saline stress on fruit production [128]. It was reported that onion (Allium cepa L.) and basil (Ocimum basilicum L.) inoculated with AMF could relieve deleterious influences of soil/water saline stress on the yield and growth of crop [129, 130]. About the leafy vegetables, in [131], it was reported that the DAOM 197198 isolate of R. intraradices might be accepted as a potential AMF candidate since it stimulated the growth of lettuce under two different saline concentrations. This influence was considered to be linked with higher leaf relative water content and lower ABA in roots, which show that AMF plants are less strained than nonmycorrhizal plants by saline conditions, which enables them to accumulate less ABA. Furthermore, in saline conditions, AM symbiosis improved the LsPIP1 expression, which involved in the transcellular water-flow regulation. A gene expression of this magnitude might contribute to regulate the root-water permeability to tolerate the osmotic stress caused by saline conditions better [132]. Hildebrandt et al. [133] reported in their study that AMF R. irregularis alleviated the deleterious influences of saline stress in lettuce (“Romana”) by changing the hormonal profiles (higher strigolactone production) and affecting plant physiology in a positive manner, which allows lettuce to grow better under harsh conditions. Gadkar and Rillig [134] reported that AMF (G. iranicum var. tenuihypharum sp. nova) could alleviate the negative influence of irrigation with high saline water on physiological parameters (photosynthesis and stomatal conductance) in lettuce. The results of research on the physiological effects of some vegetable species related to the benefits of mycorrhizae in salt stress conditions are presented in Table 2.
Activity of catalase (CAT), glutathione reductase (POD), and ascorbate peroxidase (APX) in leaves of plants treated with mycorrhizae increased. Leaf water potential and osmotic potential has increased. Pepper plants inoculated with mycorrhizal fungi showed the highest chlorophyll content and leaf area in saline conditions. The interaction between mycorrhizal fungi and plants occur higher photosynthesis activities and transpiration rates pursuing with stomatal conductivity.
More ACC deaminase has been detected in plants treated with G. mosseae.
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Table 2.
Summary of reported physiologic effects of mycorrhizae under salinity stress conditions on different vegetables.
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3.2. Drought
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Climate change is defined as the changes observed over many years in the average state of the climate regardless of its cause. Today’s climate change depends on the greenhouse effect of gases released to the atmosphere due to fossil fuels, improper land use, deforestation, and industrial development, but it is not caused by natural factors, as it has been since the formation of the world. The primary effect of this change, in which the direct human factor plays a role, is the increase in mean surface temperatures, in other words global warming. Modeling efforts to understand global climate change predicts that the average global warming will increase by 1–3.5°C by 2100 and that there will be regional extreme temperatures, floods, and widespread and severe droughts all over the world. Drought is related to the amount of water that can be taken by the roots during the growth period of the plant which is added to the field rather than the total amount of rainfall that occurs throughout the year. Plants that are experiencing water deficiency during the growing period face with significant losses in terms of development and especially yield [143, 144]. Measures should be taken as soon as possible to mitigate the effects of agricultural drought, since the available water resources are limited and the occupancy rate of these reserves is predicted to decrease rapidly due to the global warming-related rainfall and especially the decrease in the amount of snowfall that feeds groundwater resources. Although plant varieties belong to the same species, they may differ in their tolerance to drought.
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Plants can adapt their growth and development mechanisms in such a way that they are least likely to be affected from environmental changes, and even adapt to environmental conditions when they grow in the same climatic conditions for long periods of time. Drought is one of the abiotic stress conditions which mostly affects the growth and development of plants [145]. Water constitutes 50% of the fresh weight of the trees and 89–90% of the other plants [146]. Plant growth is affected considerably in arid conditions. This effect in growth depends on the length of time the water stress is experienced. In the early stages of arid conditions, the plant slows elongation and triggers root development to reach more water. On the other hand, if arid conditions last long enough to cause damage to the plant, both stem and root growth will stop, leaf area and number of leaves will decrease, and even some leaves turn yellow. The decline in plant growth is due to the division of cells in the shoot and root meristems and the arrest of expansion of the cells. The disruption of cell division or enlargement is directly related to the decrease in the rate of photosynthesis due to water insufficiency [147]. When the plants are exposed to drought stress, the water balance between the tissues is disturbed. In case of stress, cell growth is negatively affected by the loss of turgor, so the cells remain small. The decrease in cell growth also affects the synthesis of the cell wall. While protein and chlorophyll are adversely affected, it is observed that the seeds lose their germination ability [148, 149, 150]. Photosynthesis and respiration slow down and stop. Decrease in cell growth causes the leaves to shrink and the production of photosynthesis to decrease further [151]. Water deficiency causes the formation of various reactive oxygen derivatives (ROD) such as superoxide radical (O2−), hydrogen peroxide (H2O2), hydroxyl radicals (OH) and superoxide radical (O2−) [152]. ROD damages membrane lipids, nucleic acids, proteins, chlorophyll, and macromolecules in the cell. The effect of free oxygen radicals on the cell membrane depends on lipid peroxidation. Lipid peroxidation, which leads to cell membrane destruction, produces malondialdehyde (MDA) as a result of several reaction steps. Drought stress also has an important effect on enzyme activity and enzyme amount in plants. In addition, the amount of abscisic acid is 40 times higher in the leaves, while in other organs including the root, this increase is less. Abscisic acid prevents the transpiration of water by closing the stomata [153].
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3.2.1. Inducing drought stress tolerance through inoculation of PGPR
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Drought affects almost every climatic region in the world and more than half of it is prone to drought each year. Drought limits the growth and the production of crops as one of the most important stresses. The response to drought by plants is at cellular and molecular level. Drought stimulates the ethylene production in the tissues of plants as it is the case in some other environmental factors and also causes abnormal growth in plants. According to [154], ACC deaminase PGPR Achromobacter piechaudii ARV8 increases the fresh-dry weights in tomato and pepper seedlings at a great deal under transient water stress. Also, these bacteria decreased the ethylene production in tomato seedlings under water stress. In water stress, the bacteria had no effects on the water content of plants, and enhanced the recovery of plants if irrigation was started again. It is interesting that when bacteria were given to the tomato plants, the plant growth continued under water stress and also when irrigation was started again. Giri et al. [155] investigated the physiological response of peas (Pisum sativum L.) to inoculation with ACC deaminase bacteria Variovorax paradoxus 5C-2 in moisture stress and watering conditions. Bacterial effects were more obvious and consistent in controlled soil drying process (moisture stress conditions). In trials that had short time periods, it was seen that ACC deaminase bacteria had positive influences on root-shoot biomass, leaf area, and plant transpiration. In trials that had long time periods, it was seen that the plants that were inoculated with ACC deaminase bacteria produced more seed yields (25–41%), seed numbers, and seed nitrogen accumulations than the plants that were uninoculated. In addition to these, the inoculation caused that the nodulation in pea plants under drought was restored to uninoculated plant levels that were well-watered. In recent years, similar results were reported. According to the recent reports, the inoculation with ACC deaminase bacteria eliminated the influences of water stress on growth, yield, and ripening of Pisum sativum L.—although partly—pot and field experiments. The results of the physiological effects of some studies related to the benefits of PGPRs on vegetables in drought stress are given in Table 3.
PGPR treatments increased seedling length, stem diameter, leaf area, and leaf dry matter at ratios of 7.85%, 42.56%, 18.12% and 41.98%, respectively, compared to the control. Except for Na, the mineral element content was also increased with PGPR treatments.
Plant growth, total and marketable yield increased by Bacillus megaterium var. phosphaticum.
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Table 3.
Summary of reported physiologic effects of plant growth promoting rhizobacteria (PGPR) under drought stress conditions on different vegetables.
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3.2.2. Drought stress tolerance through mycorrhizae
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Arbuscular mycorrhizae (AM) symbiosis is associated with enhancing the resistance to water and drought stress despite the change of plant physiology and the expression of plant genes [120, 160]. It was reported in previous studies that AM-related increase in drought tolerance involved increased dehydration and dehydration tolerance [161]. AM fungi inoculation was able to reduce the leaf content of malondialdehyde and soluble protein and improve the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), which resulted in enhanced osmotic adjustment and drought tolerance of mycorrhizae citrus-grafting seedlings [162]. Inoculation of Glomus versiforme in citrus plants enhanced the osmotic adjustment of the plant in drought stress via improved levels of non-structural carbohydrates, K(+), Ca(+), and Mg(2+), which resulted in improvement of drought tolerance [163].
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It was reported that the role of abscisic acid (ABA) was behind the AM-related stress response in plants [164]. When exogenous ABA was added, the ABA content was improved in shoots of non-AM plants, concomitant with the expression of the stress marker genes Lsp5cs and Ls1ea and the gene Lsnced. However, when exogenous ABA was added, the ABA content in AM shoots decreased, and this addition did not cause more improvement of the expression. Co-inoculation of lettuce with PGPR Pseudomonas mendocina and G. intraradices or G. mosseae improved an antioxidative catalase in serious drought, which shows that they might be used in inoculants to relieve the oxidative harm [165]. A 14-3-3 protein encoding gene from Glomus intraradices growing in vitro and subjected to drought stress was identified [166]. The role of these proteins regulating the signaling pathways and effector proteins was claimed to impart the protection to the host plants against drought stress. Glutathione and ascorbate have a significant effect in conferring the protection and maintaining metabolic function of plants in water deficit conditions.
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AMF are known to have an efficacious and sustainable mechanism. With this mechanism, tolerance to drought is enhanced in vegetables [167, 168]. AMF cause changes in the roots of plants, especially in length, density, diameter, and number of lateral roots [169]. Improved root structure in mycorrhizae plants allows the extraradical hyphae to extend beyond depletion zones of plant rhizosphere, which makes the water and low-mobile nutrient intake (P, Zn, and Cu) more efficiently under water stress [170].
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The AM symbiosis effectiveness in improving drought tolerance was also investigated in vegetables. Open-field tomato (Solanum lycopersicum L.) inoculated with AMF (R. intraradices) influenced the agronomical and physiological responses of exposure in different drought intensities [171]. Compared to non-inoculated ones, the fruit yield of inoculated plants in severe-moderate-mild drought stresses was high at a statistically significant level by 25, 23, and 16%, respectively. It was reported in this study that high crop performance in inoculated plants was associated with better nutritional status (higher N and P) in connection with the maintenance of leaf water status. Ikiz et al. [172] confirmed this effect on tomato. They showed that the colonization of processing tomato “Regal 87-5” plants by F. mosseae and G. versiforme might increase marketable yield by 20% and 32%, respectively, when compared with those of non-inoculated plants under mild-heavy drought stress. Greenhouse melon (Cucumis melo L. “Zhongmi 3”) plants (inoculated with three Glomus species: G. versiforme and R. intraradices and, especially, F. mosseae) showed higher tolerance to drought stress than non-inoculated plants. This situation was determined in plant heights, root lengths, biomass production, and net photosynthetic rates [173]. They claimed that the increase in drought tolerance and better crop performance might be associated with the antioxidant enzyme production (SOD, POD, and CAT) and the soluble sugar accumulation by AM symbiosis. Lucy et al. [174] examined the mechanisms which affected the relief of drought by a mixture of Glomus spp. from Mexico ZAC-19 (G. albidium, G. claroides, and G. diaphanum) in Chile ancho pepper (C. annuum L. San Luis). They reported that ZAC-19 had the potential to be incorporated into Chile pepper transplant systems to relieve the harmful effect of drought in open-field production in Mexico, which was shown by high root-to-shoot rate and leaf water potential. In a similar manner, in [175] it was reported that drought enhanced bigger extraradical hyphae development of G. deserticola in bell pepper, and as a result, a high water intake, when compared to non-mycorrhizae plants. It was also reported that AMF symbiosis enhanced lettuce (Lactuca sativa L. “Romana”) tolerance to drought and recovery. This enhancement was achieved via the modification of the plant physiology and the expression of plants genes [176, 177]. Lettuce, which was inoculated with the AMF R. intraradices, gave high root hydraulic conductivity and low transpiration in drought, when it was compared with non-inoculated plants. Authors [178, 179] also emphasized that the plants inoculated with AMF could regulate their abscisic acid (ABA) concentrations in a better and quicker manner than non-inoculated plants, which allows a better balance between leaf transpiration-root water movement in drought stress and recovery [180, 181]. It was reported that inoculation with AMF enhanced WUE in watermelon [182], which shows that AMF improved water intake and resulted in the host plant making use of water in a more efficacious manner [183]. This was associated with the mechanisms that could increase transpiration and stomatal conductance [184], and also improve the availability of the nutrients [183]. The results of the physiological effects of some studies related to the benefits of mycorrhizae on vegetables in drought stress are given in Table 4.
Activity of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) in leaves of plants treated with Glomus increased.
Water-use efficiency, leaf water content, and leaf osmotic potential has increased.
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Table 4.
Summary of reported physiologic effects of mycorrhizae under drought stress conditions on different vegetables.
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4. Conclusion
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Today, the utilization of natural resources in agriculture comes to the forefront because of improving environmental awareness. The evaluation of the use of natural resources, such as mycorrhiza and a cleaner environment, is important both for economic reasons. Resources are often used as a source of plant nutrition in hydroponics. Given the chemical, the use of mycorrhiza in agriculture is very important in soil. Particularly with the use of mycorrhiza, the use of chemical fertilizers especially consisting phosphorus, can be reduced. As a conclusion, mycorrhizae are important for the growth of agricultural crops as well as healthy ecosystem functions. Many benefits of mycorrhizal symbiosis can be enhanced by changing agricultural practices which may decrease colonization and mycorrhizal abundance [194].
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Hydraheaded stress caused by biotic and abiotic reasons is threatening modern agriculture. Several stress types explained in this chapter emphasize ethylene biosynthesis, which prevents plant growth by some tools at molecular level. In this chapter, for the purpose of regulating the plant ethylene, application of PGPR with ACC deaminase is crucial. Several roles of PGPR in saline conditions, in drought, waterlogging, biocontrol, temperature and nutritional stresses and in cut-flower industry and nodulation in legumes were not investigated in detail by researchers. In commercial terms, applying PGPR with ACC deaminase in agriculture may be useful. It may also be an important progress to obtain sustainable crop production and conservation. Because of several drawbacks, genetic modification of plant species is not probable (for example, proprietary rights, trade agreements among countries for genetically modified (GM) crops, and due to the limitations in DNA recombinant technology in some areas in the world). Because of all these reasons, using PGPR with ACC deaminase activity and similar innovations may be a cost-effective and environment-friendly way for sustainable agriculture.
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\n\n',keywords:"bio-fertilizers, PGPR, mycorrhizae, vegetable, abiotic stress, salinity, drought",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60925.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60925.xml",downloadPdfUrl:"/chapter/pdf-download/60925",previewPdfUrl:"/chapter/pdf-preview/60925",totalDownloads:1373,totalViews:416,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:10,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"October 5th 2017",dateReviewed:"March 5th 2018",datePrePublished:null,datePublished:"September 26th 2018",dateFinished:"April 21st 2018",readingETA:"0",abstract:"Industrialization and rapid population growth, especially after the second half of the twentieth century, have also revealed significant environmental problems in the world. The consistent and alarming increase in the human population has again threatened the world’s food security. It is becoming increasingly clear that conventional agricultural practices cannot sustain the production base, a healthy plant-soil system, for too long. There is a growing worldwide demand for compatible environmentally friendly techniques in agriculture, capable of providing adequate nourishment for the increasing human population and of improving the quality and quantity of certain agricultural products. For these reasons, the application of beneficial microorganisms is an important alternative to some of the traditional agricultural techniques which very often severely alter the agro-ecosystem balance and cause serious damage to health. Beneficial microorganisms can play a key role in this major challenge, as they fulfill important ecosystem functions for plants and soil. Utilization of these microorganisms affects plant’s growth and yield in a positive way. Besides, their favorable effects on root growth help plants to deal with both biotic and abiotic stress factors. PGPR and mycorrhizae can influence higher plants response to abiotic stresses such as drought and salinity through different mechanisms.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60925",risUrl:"/chapter/ris/60925",book:{id:"6277",slug:"physical-methods-for-stimulation-of-plant-and-mushroom-development"},signatures:"Özlem Altuntaş and İbrahim Kutalmış Kutsal",authors:[{id:"225015",title:"Associate Prof.",name:"Ozlem",middleName:null,surname:"Altuntas",fullName:"Ozlem Altuntas",slug:"ozlem-altuntas",email:"ozaltuntas01@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"225019",title:"MSc.",name:"Ibrahim Kutalmıs",middleName:null,surname:"Kutsal",fullName:"Ibrahim Kutalmıs Kutsal",slug:"ibrahim-kutalmis-kutsal",email:"kutalmis07@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Beneficial microorganisms against stress conditions PGPR and mycorrhiza",level:"1"},{id:"sec_2_2",title:"2.1. Plant growth promoting rhizobacteria (PGPR)",level:"2"},{id:"sec_3_2",title:"2.2. Mycorrhizae",level:"2"},{id:"sec_5",title:"3. The most effective environmental stress factors: salinity and drought",level:"1"},{id:"sec_5_2",title:"3.1. Salinity stress",level:"2"},{id:"sec_5_3",title:"Table 1.",level:"3"},{id:"sec_6_3",title:"Table 2.",level:"3"},{id:"sec_8_2",title:"3.2. Drought",level:"2"},{id:"sec_8_3",title:"Table 3.",level:"3"},{id:"sec_9_3",title:"Table 4.",level:"3"},{id:"sec_12",title:"4. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Perrott KW, Sarathchandra SU, Dow BW. Seasonal and fertilizer effects on the organic cycle and microbial biomass in a hill country soil under pasture. 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Journal of Experimental Botany. 2004;55:1743-1750\n'},{id:"B161",body:'McKeon TA, Fernandez-Maculet JC, Yang SF. Biosynthesis and metabolism of ethylene. In: Davies PJ, editor. Plant Hormones Physiology, Biochemistry and Molecular Biology. Dordrecht, Netherlands: Kluwer Academic Publishers; 1995. pp. 118-139\n'},{id:"B162",body:'Gaspar T, Penel C, Hadege D, Greppin H. Biochemical, molecular and physiological aspects of plant peroxidases. In: Lobarzewski J, Greppin H, Penel C, Gaspar T, editors. Plant Peroxidases. Geneva: Imprimerie Nationale, University of Geneva; 1991. pp. 249-280\n'},{id:"B163",body:'Jasper DA, Abbot LK, Robson AD. The effect of soil disturbance on vesicular-arbuscular mycorrhizal fungi in soils from different vegetation type. The New Phytologist. 1991;118:471-476\n'},{id:"B164",body:'Egberongbe HO, Akintokun AK, Babalola OO, Bankole MO. The effect of Glomus mosseae and Trichoderma harzianum on proximate analysis of soybean (Glycine max (L.) Merrill.) seed grown in sterilized and unsterilised soil. Journal of Agricultural Extension and Rural Development. 2010;2:54-58\n'},{id:"B165",body:'Bethlenfalvay GJ, Schüepp H. Arbuscular mycorrhizas and agrosystem stability. In: Gianinazzi S, Schüepp H, editors. Impact of Arbuscular Mycorrhizas on Sustainable Agriculture and Natural Ecosystems. Basel: Birkhauser; 1994. pp. 117-131\n'},{id:"B166",body:'Denton B.. Advances in phytoremediation of heavy metals using plant growth promoting bacteria and fungi. MMG445 Basic Biotechnology. 2007;3:1-5\n'},{id:"B167",body:'del Rio LA, Sandalio LM, Altomare DA, Zilinskas BA. Mitochondrial and peroxisomal manganese superoxide dismutase: Differential expression during leaf senescence. Journal of Experimental Botany. 2003;54:923-933\n'},{id:"B168",body:'Mehraban A, Vazan S, Naroui MR, Ardakany AR. Effect of vesicular-arbuscular mycorrhiza (VAM) on yield of sorghum cultivars. Journal of Food, Agriculture and Environment. 2009;7:461-463\n'},{id:"B169",body:'Pamp SJ, Tolker-Nielsen T. Multiple roles of biosurfactants in structural biofilm development by Pseudomonas aeruginosa. Journal of Bacteriology. 2007;189:2531-2539. DOI: 10.1128/JB.01515-06\n'},{id:"B170",body:'Qurashi AW, Sabri AN. Bacterial exopolysaccharide and biofilm formation stimulate chickpea growth and soil aggregation under salt stress. Brazilian Journal of Microbiology. 2012;43:1183-1191. DOI: 10.1590/S1517-83822012000300046\n'},{id:"B171",body:'Suslow TV, Schroth MN. Role of deleterious rhizobacteria as minor pathogens in reducing crop growth. Phytopathology. 1982;72:111-115\n'},{id:"B172",body:'Ikiz O, Abak K, Dasgan HY, Ortas I. Effects of mycorrhizal inoculation in soilless culture on pepper plant growth. Acta Horticulturae. 2006;2(807):533-541\n'},{id:"B173",body:'Giri B, Kapoor R, Mukerji KG. Improved tolerance of Acacia nilotica to salt stress by arbuscular mycorrhiza, Glomus fasciculatum may be partly related to elevated K/Na ratios in root and shoot tissues. Microbial Ecology. 2007;54:753-760\n'},{id:"B174",body:'Lucy M, Reed E, Glick BR. Application of free living plant growth promoting rhizobacteria. Anton de Leeuw. 2004;86:1-25\n'},{id:"B175",body:'Kothari SK, Marschner H, George E. Effects of VA mycorrhial fungig and rhizosphere organisms on root and shoot morphology, growth and water relation in maize. New Phytologist. 1990;116:303-311\n'},{id:"B176",body:'Kotan R, Fikrettin S, Erkol D, Cafer E. Biological control of the potato dry rot caused by Fusarium species using PGPR strains. Biological Control. 2009;50:194-198\n'},{id:"B177",body:'McArther DAJ, Knowles NR. Influence of VAM and phosphorus nutrition on growth, development and mineral nutrition of potato. Plant Physiology. 1993;102:771-782\n'},{id:"B178",body:'Saravanakumar D, Harish S, Loganathan M, Vivekananthan R, Rajendran L, Ragu-chander T, et al. Rhizobacterial bioformulation for the effective management of Macrophomina root rot in mung bean. Archives of Phytopathology and Plant Protection. 2007;40:323-337\n'},{id:"B179",body:'Alizadeh H, Behboudi K, Ahmadzadeh M, Javan-Nikkhah M, Zamioudis C, Pieterse CMJ, et al. Induced systemic resistance in cucumber and Arabidopsis thaliana by the combination of Trichoderma harzianum Tr6 and Pseudomonas sp. Ps14. Biological Control. 2013;65:14-23\n'},{id:"B180",body:'Ait Barka E, Nowak J, Clement C. Enhancement of chilling resistance of inoculated grapevine plantlets with a plant growth-promoting rhizobacterium, Burkholderia phytofirmans strain PsJN. Applied and Environmental Microbiology. 2006;72:7246-7252\n'},{id:"B181",body:'Abak K, Dasgan HY, Rehber Y, Ortaş I. Effect of vesicular arbuscular mycorrhizas on plant growth of soilless grown muskmelon. Acta Horticulturae®. In: IV International Symposium on Cucurbits. Vol. 871. 2009. pp. 301-306\n'},{id:"B182",body:'Jiao H, Chen Y, Lin X, Liu R. Diversity of arbuscular mycorrhizal fungi in greenhouse soils continuously planted to watermelon in North China. Mycorrhiza. 2011;21(8):681\n'},{id:"B183",body:'Ruiz-Lozano JM, Azcon R, Gomez M. Alleviation of salt stress by arbuscular-mycorrhizal Glomus species in Lactuca sativa plants. Physiologia Plantarum. 1996;98(4):767-772\n'},{id:"B184",body:'Nelson R, Achar PN. Stimulation of growth and nutrient uptake by VAM fungi in Brassica oleracea var. capitata. Biologia Plantarum. 2001;44(2):277-281\n'},{id:"B185",body:'Turrini A, Sbrana C, Nuti MP, Pietrangeli BM, Giovannetti M. Development of a model system to assess the impact of genetically modified corn and aubergine plants on arbuscular mycorrhizal fungi. Plant and Soil. 2005;266(1-2):69-75\n'},{id:"B186",body:'Ortas I, Sari N, Akpinar C, Yetisir H. Screening mycorrhiza species for plant growth, P and Zn uptake in pepper seedling grown under greenhouse conditions. Scientia Horticulturae. 2011;128(2):92-98\n'},{id:"B187",body:'Huang Z, Zou Z, He C, He Z, Zhang Z, Li J. Physiological and photosynthetic responses of melon (Cucumis melo L.) seedlings to three Glomus species under water deficit. Plant and Soil. 2011;339(1-2):391-399\n'},{id:"B188",body:'Varga SS, Koranyi P, Preininger E, Gyurjan I. Artificial associations between Daucus and nitrogen-fixing Azotobacter cells in vitro. Physiologia Plantarum. 1994;90(4):786-790\n'},{id:"B189",body:'Auge RM. Water relations, drought and vesicular-arbuscular mycorrhizal symbiosis. Mycorrhiza. 2001;11:3-42\n'},{id:"B190",body:'Cho K, Toler H, Lee J, Ownley B, Stutz JC, Moore JL, et al. Mycorrhizal symbiosis and response of sorghum plants to combined drought and salinity stresses. Journal of Plant Physiology. 2006;163:517-528\n'},{id:"B191",body:'Berreck M, Haselwandter K. Effect of the arbuscular mycorrhizal symbiosis upon uptake of caesium and other cations by plants. Mycorrhiza. 2001;10:275-280\n'},{id:"B192",body:'Sannazzaro AI, Ruiz OA, Alberto EO, Menendez AB. Alleviation of salt stress in Lotus glaber by Glomus intraradices. Plant and Soil. 2006;285:279-287\n'},{id:"B193",body:'Seymen M, Turkmen O, Dursun A, Paksoy M. Effects of bacteria inoculation on yield, yield components and mineral contents of tomato. Journal of Selcuk Agriculture and Food Science. 2015;28(2):52-57\n'},{id:"B194",body:'del Amor FM, Cuadra-Crespo P. Plant growth-promoting bacteria as a tool to improve salinity tolerance in sweet pepper. Functional Plant Biology. 2012;39(1):82-90\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Özlem Altuntaş",address:"ozlem.altuntas@inonu.edu.tr",affiliation:'
Faculty of Agriculture, Department of Horticulture, Inonu University, Malatya, Turkey
Faculty of Agriculture, Department of Horticulture, Inonu University, Malatya, Turkey
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1. Introduction
CD4+ T cells, also called helper T cells, are important regulators of adaptive immune responses, which are antigen-specific and critical in protecting animals from pathogen infections. The control of intracellular pathogens, such as viruses, primarily depends on antigen-specific CD8+ T cell response, whereas antibodies (produced by B cells) or humoral immune responses are mostly responsible for the control of extracellular pathogens such as most bacteria and parasites. CD4+ T cells are the lynchpin in shaping both CD8+ T cell and antibody responses [1, 2].
Common lymphoid progenitor cells migrate from the bone marrow into the thymus for further development and maturation into T cells. Inside the thymus, these progenitor cells proliferate into a large pool of T cells, with each expressing a unique T cell receptor (TCR) through a genetic recombination. After TCR recombination, T cells must go through two selection processes, and only a fraction of them pass through these selections and become either CD4+ or CD8+ T cells [3]. Surviving CD4+ T cells then exit the thymus as naïve CD4+ T cells but without the ability to help CD8+ T cells and B cells. To become fully functional, naïve CD4+ T cells need to become activated and differentiated into specialized effector subtypes; helper type 1 (Th1) to facilitate CD8+ T cell responses, and helper type 2 (Th2) to facilitate antibody responses [4]. Naïve CD4+ T cells constantly survey secondary lymphoid tissues to detect pathogens through their antigen-specific TCRs [5]. As opposed to antibodies, which bind directly to pathogens or their derivatives, TCRs can only recognize short chains of amino acids (derived from pathogens) that are presented by major histocompatibility-II (MHC-II) expressed on antigen presenting cells (APCs) [2]. This recognition process provides the 1st signal required to activate naïve CD4+ T cells. Along with the 1st signal, APCs also offer co-stimulation as the 2nd signal and cytokine signaling, as the 3rd signal, to the naïve CD4+ T cell. Combined, these three signals coordinate CD4+ T cell differentiation into distinct effector subtypes with different helper functions [2].
Studies in humans and mice have identified numerous helper subtypes, including: Th1, Th2, Th3, Th9, Th17, Treg, and Tr1 [2, 6]. Among these, Th1 and Th2 are considered to play major roles in defending the host from pathogen invasion [7, 8, 9]. Th1 cells help CD8+ T cells to gain killing functions, which leads to apoptosis of infected cells and induces Interferon gamma (IFNγ) mediated immunity [10, 11, 12, 13]. On the other hand, Th2 cells help B cells differentiate into plasma cells, which produce pathogen-specific antibodies [14]. Antibodies or humoral immunity contribute to the control of extracellular pathogens by mechanisms like neutralizing toxins, preventing bacterial attachment to the host cell, and stimulating basophil and mast cells to release toxic chemicals that induce the expulsion of large gastrointestinal parasites [15, 16]. Although antibodies are mostly responsible for controlling extracellular pathogens, they can also play important roles in cell-mediated killing of intracellular pathogens [17]. For instance, during intracellular infections in mice, Th1 cells help B cells become plasma cells that secrete antigen- specific immunoglobulin subtype G2a (IgG2a), which in turn can help killing infected cells through antibody dependent cytotoxicity (ADCC) [18, 19]. In short, Th1 is responsible for control of intracellular pathogens mostly through shaping CD8+ T cell responses and Th2 is for control of extracellular pathogens through antibody responses. In addition, antibodies can be involved in both Th1 and Th2 responses, but with unique subtypes, such as IgG2 for Th1, and IgG1 for Th2 in cattle. This will be discussed further in Section 2.
There are many similarities in the immune system across species. Therefore, knowledge generated from the research in mice and humans has been extensively applicable to study immune responses in cattle [20, 21, 22, 23]. In the past several decades, however, unique features have been discovered in the bovine immune system that are not shared with that of mice and humans, such as high prevalence of circulating γδ T cells [24], production of IL-10 by γδ T cells [25], regulation of CD4+ T cell activation by neutrophils [26], which are able to secrete IL-10, and high prevalence of hybrid helper T cells (i.e., co-express both Th1 and Th2 cytokines), which is relatively low in humans and mice [22, 27, 28].
Cattle industry suffers billions of dollar’s losses annually due to infections, and many of the commercially available vaccines for cattle are not fully effective [29, 30, 31, 32]. Understanding the mechanisms underlying bovine CD4+ T cell differentiation, which seems to be partially different from that of mice and humans, is critical to identify novel strategies to achieve more effective immunity after vaccinations, such as through generating strong Th1 responses against intracellular pathogens and Th2 responses against extracellular pathogens. In this chapter, we will summarize the current knowledge and key findings on bovine CD4+ T cell responses, highlight the existing knowledge gaps, and provide some insights on future directions.
2. CD4+ T cells regulate adaptive immunity
Naive CD4+ T cells exit the thymus and search for pathogen-derived antigens presented by APCs in secondary lymphoid tissues (e.g., lymph nodes and the spleen). During infections, pathogens break through barriers (Physical, chemical etc) of the host to establish infection in the local tissues [33]. As a result, the immune system in the host initiates an inflammatory response through recruitment of immune cells such as neutrophils to the site of infection, which secretes inflammatory cytokines and chemokines [34, 35]. These chemokines provide signals for further recruitment of APCs to the site of infection. APCs constantly search for invading pathogens through recognizing pathogen associated molecular patterns (PAMPS) on pathogens by their pattern recognition receptors (PRRs) [36]. For example, Toll-like receptor-4 (TLR-4) on APCs can recognize the lipopolysaccharide (LPS) present on the cell membranes of gram-negative bacteria [37]. After recognition, APCs engulf the pathogen, break it down into small peptides, and finally present the peptides to CD4+ T cells in the secondary lymphoid tissue. Recognition of this peptide–MHC-II complex by the TCRs on the naïve CD4+ T cells provides the 1st activation signal, as shown in Figure 1 [41]. At the same time, co-stimulatory molecules on the CD4+ T cell surface (e.g., CD28) recognize their corresponding ligands on the APC surface (e.g., CD80 or CD86), which provides the 2nd activation signal [42]. The final and 3rd signal, which occurs simultaneously with antigen stimulation and co-stimulation, is provided by cytokines such as Interleukin-12 (IL-12) or Interleukin-4 (IL-4) that not only enhance the activation process, but also drive CD4+ T cell differentiation into a specific subtype (e.g., Th1 or Th2) [2, 43]. Therefore, APCs can provide all 3 signals to naïve CD4+ T cells, which facilitates their activation and differentiation (Figure 1). Pathogens can regulate host helper T cell response through targeting any of the three signals directly or indirectly, which will be discussed in Section 5. Recently, we have reported that bovine CD4+ T cells respond to three signals in a way similar to that in humans and mice [44]. Furthermore, IL-12 and neutrophils can work on bovine CD4+ T cells synergistically to enhance their production of IFNγ [44].
Figure 1.
Three-signal model for CD4 + T cell activation: The 1st signal is provided when TCRs recognize the peptide–MHC-II complex presented by APC; the 2nd signal is initiated when CD28 on CD4+ T cells interacts with CD80/86 on APCs, and the 3rd signal is triggered by cytokines released from the APCs and other cells. CD28/CD80/CD86 interaction is used as an example. This figure was adapted from previous reviews [38, 39, 40].
2.1 Th1 cells coordinate CD8+ T cell response to intracellular pathogens
During the infection, the host responds to the intracellular pathogens by inducing cytokines such as IFNγ and IL-12 from APCs like macrophages and dendritic cells (DCs), which further leads to the polarization of CD4+ T cells into a Th1 subtype. IFNγ and IL-12 enhance the expression of transcription factor T-bet, which directs Th1 differentiation in the activated naïve CD4+ T cells (Figure 2a) [51, 52]. More specifically, when bound to their receptors on naïve CD4+ T cells, these cytokines induce the activation of transcription factor STAT-1 or STAT-4 respectively, which in turn causes T-bet upregulation [53]. Subsequently, T-bet induces histone modification and binds to the promoter region of Th1-specific cytokine genes, which leads to enhanced expression of IFNγ [51, 52]. In addition, T-bet also inhibits Th2 differentiation by repressing the transcription of Th2 specific genes, such as GATA-3, which is the transcription factor responsible for IL-4 expression [51, 54]. Thus, IFNγ and IL-12 induce Th1 differentiation, which leads to IFNγ production and suppression of Th2 differentiation.
Figure 2.
Th1 help to the activation of CD8+ T cell. A) IFNγ and IL-12 bind to their corresponding receptors on naïve CD4+ T cells during activation, which leads to T-bet expression and Th1 differentiation. This figure was adapted from previous reviews [45, 46, 47]. B) Once differentiated, Th1 effector cell conditions dendritic cell, which in turn activates CD8+ T cell. This figure was adapted from previous reviews [48, 49, 50].
One key functions of differentiated Th1 cells is to facilitate the activation of CD8+ T cells by “conditioning” dendritic cells; a process that induces dendritic cell (DC) maturation by modifying their cytoskeletal structure, upregulating co-stimulatory molecules, and by enhancing their migration to secondary lymphoid tissues [55, 56, 57]. Once conditioned, these DCs can induce CD8+ T cell activation as shown in Figure 2(b). Although these two processes, conditioning of DCs and activation of CD8+ T cells, might occur simultaneously, some researchers argue that this process may occur in two sequential steps: conditioning DC first, followed by CD8+ T cell activation [56, 58, 59]. Activated CD8+ T cell secretes cytotoxicity-related proteins such as perforin and granzyme-B. While perforin forms pores at the cell membrane, granzyme enters through these pores and cause apoptosis of the infected cell [60]. Additionally, antigen-specific CD8+ T cells can kill infected cells through caspase mediated pathway, when Fas molecules expressed on the infected cells interact with Fas Ligand expressed on the antigen-specific CD8+ T cells [61].
IFNγ is a critical cytokine performing multiple functions to assist Th1 response against intracellular pathogens in mice, humans and cattle [62]. Although many types of immune cells can produce IFNγ including NK cells, DCs, macrophages and B cells, it is the signature cytokine of Th1 subtype [27]. Th1 produced IFNγ plays a critical role in regulating the Th1 response. IFNγ can recruit immune cells to the site of infection and promote anti-microbial activities of neutrophils and macrophages by inducing oxidative burst and production of reactive oxygen species (ROS) [62, 63, 64, 65]. IFNγ is directly involved in blocking viral replication, as well as enhancing the cytotoxic activity of CD8+ T cells [66, 67]. Moreover, IFNγ can enhance the number, mobility, and cytotoxicity of CD8+ T cells [67, 68].
During infection caused by intracellular pathogens, Th1 produced IFNγ can induce IgG subtype switching in activated B cells. However, this subtype switching may differ among the species. For example, it induces production of IgG2a in mice and IgG2 in cattle but IgG1 and IgG3 in humans (Table 1) [18, 69, 73]. These IgG subtypes induced by IFNγ can facilitate multiple mechanisms such as ADCC to kill intracellular pathogens, such as Coxiella burnetii, Listeria monocytogenes, and Toxoplasma gondii in mice [19, 82].
Th1- and Th2-associated IgG subtypes in mice, humans, and cattle.
2.2 Differentiated Th2 cells coordinate humoral response against extracellular pathogens
During infections caused by extracellular pathogens, innate immune cells such as basophils, eosinophils, and innate lymphoid cells (ILCs) produce and secrete IL-4 [83, 84]. Together with 1st and 2nd signals, IL-4 signaling on naïve CD4+ T cell upregulates GATA-3 (GATA binding protein-3), a critical transcription factor for Th2 differentiation [85, 86]. GATA-3 knockout mice mounted impaired Th2 responses [87, 88]. When IL-4 binds to its corresponding receptor on the surface of naive CD4+ T cells, it activates STAT-6, which turns on pathways leading to GATA-3 expression (Figure 3a) [93, 94]. Consecutively, GATA-3 promotes Th2 differentiation by inducing histone acetylation and enhancing transcription of the IL4 gene [83, 95]. In addition, GATA-3 is capable of suppressing Th1 differentiation by downregulating transcription and expression of molecules such as the IL-12 receptor β2, IFNγ, STAT-4, and possibly T-bet [96].
Figure 3.
Th2 help to the activation of B cell. A) IL-4 binds to its receptor on naïve CD4+ T cells during activation, which induces GATA-3 activation and Th2 differentiation. This figure was adapted from previous reviews [46, 89, 90]. B) Once differentiated, Th2 cells secrete IL-4 and provide antigen stimulation and co-stimulation to a B cell. This figure was adapted from previous reviews [91, 92].
Once differentiated, Th2 cells are capable of activating B cells to produce antibodies that defend the host against extracellular pathogens [97, 98]. During B cell activation, Th2 cells recognize peptide–MHC-II complexes expressed on B cells [99, 100] and provide co-stimulation via CD40L, which are both necessary for B cell activation [101] (Figure 3b). Importantly, IL-4 signaling induces isotype and subtype switching of B cells towards IgE and IgG1 production, which are key antibodies for controlling extracellular pathogens in mice and cattle [102].
Although antibodies can assist CD8+ T cell responses during intracellular infections, they play a major role in controlling infections caused by extracellular pathogens [13, 103, 104]. Antibodies can prevent the attachment of extracellular bacteria to the host cell, facilitate phagocytic killing, and neutralize toxins [13, 105, 106, 107, 108]. In addition, different antibody isotypes and subtypes can have different functions. For instance, IgE can bind to both low and high-affinity receptors (FcεRI and FcεRII) on mast cells and basophils, which results in the degranulation and release of chemicals (e.g., histamine, leukotrienes) that either kill parasites directly, or induce hyper-contraction of intestinal smooth muscle to promote their expulsion [109, 110, 111, 112].
In addition to IL-4, other cytokines such as IL-5, IL-9 and IL-13 are also involved in the control of extracellular pathogens. For example, IL-9 promotes production of IgE and proliferation as well as maturation of mast cells, which rapidly infiltrate the site of infection [113, 114]. Similarly, IL-5 induces differentiation, maturation, and infiltration of eosinophils to the site of infection [114]. Infiltrated mast cells and eosinophils, when cross-linked by antigen-specific IgE, degranulate (i.e., release histamine and leukotrienes) to kill or expel gastrointestinal parasites. IL-13 on the other hand, plays a significant role in the expulsion of parasites by inducing regeneration of the intestinal epithelium and contraction of smooth muscle cells in the intestine [98, 115]. Nevertheless, there are multiple cytokines involved in the differentiation of Th2 responses, but IL-4 is considered the most critical one.
2.3 Th1/Th2 cytokines induce immunoglobulin class switching during infection
Antibodies produced by activated B cells during infection are classified into five different classes (i.e., IgM, IgG, IgA, IgD and IgE) based on their structure [116]. Among them, IgG is the most abundant in serum, and it has four different subtypes, namely: IgG1, IgG2, IgG3 and IgG4 [116]. Each antibody has two structural segments (heavy and light chains) and two functional segments (Fab and Fc portions). While association of heavy chain with the light chain at the Fab portion forms antigen-binding sites, only the constant portion of the heavy chain constitutes the Fc segment that regulates the effector function of the antibody. During infection, activated B cells undergo isotype or subtype switching, a process that involves switching of Fc segment but not of the Fab segment. Briefly, DNA in B cells contains multiple heavy chain constant genes (or CH genes) that encode various types of Fc segments [117]. During infections, Th1 and Th2 cytokines provide signals to the activated B cells to select a specific CH gene for the heavy chain, thus producing a specific isotype or subtype of immunoglobulins with the same antigen specificity [118]. For example, IFNγ can induce subtype switching to IgG2a to enhance the killing of infected cells in mice; similarly, IL-4 can induce switching to IgG1 to promote humoral immunity (Table 1) [70, 71, 72, 119]. Historically, characterizing serum IgG subtypes was a common practice to define the immune response in clinically ill cattle; the greater concentration of serum IgG2 typically indicated a Th1 response, whereas greater IgG1 indicated a Th2 response. Interestingly, the Th1 induced IgG subtypes may vary among the mice, humans and cattle species as shown in Table 1.
2.4 Cytokines and transcription factors mediate Th1/Th2 cross-regulation
In humans and mice, multiple lines of evidence support that Th1 differentiation inhibits Th2 differentiation, and vice versa [120, 121]. For example, in vitro experiments reveal that IFNγ inhibits Th2 differentiation whereas IL-4 suppresses Th1 differentiation [122, 123, 124]. In addition, studies using knockout mice and retroviral-transduced CD4+ T cells demonstrate that T-bet blocks Th2 differentiation by inhibiting the transcription of genes associated with Th2 cytokine production [54, 125]. Similarly, GATA-3 prevents Th1 differentiation by suppressing the transcription of genes associated with Th1 cytokines, and interfering with Th1-promoting transcription factors [126, 127]. Collectively, these findings confirm that Th1 and Th2 transcription factors and cytokines cross-regulate each other, ensuring that CD4+ T cells differentiate into either Th1 or Th2 cells. In cattle, however, most of the differentiated clones represent a “hybrid” that co-expresses both IFNγ and IL-4 in the same cell (explained in detail in Section 3) [22, 128]. While it is clear in mice and humans that T-bet and GATA-3 are the transcription factors that regulate expression of IFNγ and IL-4 respectively, at this moment, it is unclear if this is equally true for cattle. In addition, we do not know if the co-production of both Th1 and Th2 cytokines in the hybrid bovine clones corresponds to the co-expression of both transcriptional factors. Therefore, further research is needed to understand the underpinning regulatory mechanism of hybrid clone differentiation in cattle.
2.5 Distinct Th1 and Th2 are the most dominant antigen-specific clones in mice and humans
In mice and humans, Mosmann et al. and Romagnani et al. stimulated single CD4+ T cells in vitro and established antigen-specific CD4+ T cell clones, which they classified mostly into Th1 and Th2 subtypes. Although, in both mice and humans, clear-cut Th1 or Th2 were the dominant clones, a small percentage of hybrid clones (named “Th0” clones), that co-produced Th1 and Th2 cytokines (IFNγ and IL-4), were also observed [27, 28]. Subsequently, follow-up research verified the existence of these hybrid clones, which were only a small fraction of the total clones (i.e., only 9.6% clones were Th0) [124, 129, 130, 131, 132, 133, 134, 135]. Therefore, at this moment, the consensus in the fields of murine and human immunology is that Th1 and Th2 are the major effector cells that orchestrate immune responses against intracellular and extracellular pathogens, respectively, and that Th0 are short-lived “intermediate” cells [131, 136, 137].
2.6 Th0 is the most dominant antigen-specific clone in cattle
Just a few years after the discovery of the Th1/Th2 subtypes in humans and mice, Brown et al. successfully investigated bovine Th1/Th2 response through the establishment and analysis of antigen-specific CD4+ T cell clones. Peripheral blood mononuclear cells (PBMC) were purified from cattle challenged by experimental pathogens: either intracellular pathogens (Babesia bovis, Babesia bigemina) or extracellular pathogens (Fasciola hepatica) [22]. These purified PBMCs (that contained pathogen-specific CD4+ T cells), were stimulated with antigens derived from the same pathogen used for the challenge, to generate pathogen-specific CD4+ T cell clones, which were then analyzed and classified based on the detection of Th1/Th2 cytokine mRNA. The authors reported that, regardless of the type of pathogen used in the challenge, most bovine clones were Th0 that co-expressed IFNγ and IL-4 (e.g., more than 60% Babesia species -specific and more than 90% Fasciola hepatica-specific clones were Th0) [22]. These observations indicated that bovine Th1/Th2 responses might be at least partially different from the typical murine and human Th1/Th2 responses, as the frequency of bovine Th0 clones was significantly higher than that of murine and humans. Later, when researchers used the Th0 clones specific to an antigen of Babesia bigemina to stimulate B cells in vitro, both, Th1-related IgG2 and Th2-related IgG1 were detected in the supernatant culture, suggesting that Th0 is capable of performing functions of both Th1 and Th2 cells [138].
3. Many critical bovine pathogens induce Th0 responses
In cattle, mixed Th1/Th2 cytokines (both IFNγ and IL-4) have been detected in cultured PBMCs, or Draining Lymph Nodes (DLNs), or local tissues in large number of diseases. Most researchers commonly refer to this as the bovine Th0 response, which may include clones of all three types (Th1, Th2, and Th0) [128, 139, 140, 141]. It is important to note that while Th0 clones can produce both IFN γ and IL-4, Th1 and Th2 clones can only produce a single cytokine, either IFN γ or IL-4 (Figure 4). Therefore, a mixed population of Th1, Th2, and Th0 cells possibly contributes to the induction of Th0 responses in most of the bovine diseases as explained in Section 4.
Figure 4.
Helper T cell responses to infections in cattle. Pathogen infections in cattle may induce three types of CD4+ T cell responses: Th1, Th2 and Th0. Th1 responses are characterized by Th1 clones that produce IFNγ, Th2 responses include Th2 clones that produce IL-4, and Th0 response could induce mixed populations of clones: Th1, Th2 and Th0. Th0 clones co-express both IFNγ and IL-4.
4. Advancement of technology facilitates the progress in bovine immunology
Technology is a critical factor that drives the advancement of science, and bovine immunology is not an exception, particularly regarding bovine CD4+ T cell research. In the late 80s, the study of bovine Th1/Th2 responses depended heavily on the measurement of cytokines in the supernatant of cultured CD4+ T cells through simple biological assays such as ELISA, or detection of IgG subtypes in the serum of infected animals through ELISA or immunoblotting techniques. In this context, upregulation of supernatant IFNγ and serum IgG2 would represent a Th1 response, upregulation of IL-4 and detection of serum IgG1 would indicate a Th2 response [18, 80], and detection of both cytokines and both IgG subtypes (IgG1 and IgG2) would represent a Th0 response [142]. In the late 90s, advancements in molecular biology enabled scientists to measure cytokines at the transcriptional level (mRNA). Thus, reverse transcription polymerase chain reaction (RT-PCR) was commonly used to detect the presence of mRNA of Th1/Th2 cytokines in PBMCs, DLNs, and tissues of infected cattle [143, 144, 145]. In the next decade, the advent of quantitative PCR (qPCR) improved the detection of Th1/Th2 transcripts from a qualitative to a quantitative level [146]. Later, with the invention and use of flow cytometry, scientists were able to measure protein production of Th1/Th2 cytokines on a population level [147]. More recently, some very exciting technological advancements have been developed, such as single-cell RNA sequencing, proteomics, metabolomics, confocal microscopy, which are considered excellent tools for a deeper understanding of immune mechanisms [148, 149, 150, 151, 152]. Therefore, the advancement of bovine immunology research is closely associated with the development of novel technology in science, especially in the context of understanding Th1/Th2 responses in cattle.
4.1 Most intracellular pathogens induce either a Th1 or Th0 response in cattle
During pathogen invasion, the host mounts a CD4+ T cell response that may or may not be effective enough to clear the infection. In humans, ineffective CD4+ T cell responses are associated with increased pathogenesis and progression towards chronic infections [153]. Cattle mostly launch either Th1 or Th0 responses against intracellular pathogens [154, 155, 156, 157]. However, some bovine pathogens are able to establish chronic infections, which is possibly associated with ineffective CD4+ T cell responses [128, 158].
As observed in mice and humans, bovine Th1 responses are considered to be protective against diseases caused by intracellular pathogens such as Theileria annulata, and Anaplasma marginale [154, 155]. Indeed, researchers in the late 80s found that transferring serum from an immune animal into animals infected with theileriosis was not effective at controlling infection [159]. Several groups later discovered that CD8+ T cell responses but not humoral responses were effective at controlling disease, since antigen-specific CD8+ T cells from recovered animals demonstrated effective cytotoxicity to the autologous infected cells in vitro [160, 161, 162]. Further research revealed that in vitro activation of T cells with Theileria-infected macrophages predominantly induced IFNγ expression [163]. Similar to theileriosis, Th1 responses were also protective against Anaplasma marginale [155, 164]. In both infected and vaccinated animals, circulatory IFNγ levels were higher relative to their healthy counterparts [155, 164]. Similarly, IgG2 was increased in cattle infected with Anaplasma marginale [165]. Collectively, in both theileriosis and anaplasmosis, hosts seem to induce effective Th1 responses.
Bovine pathogens such as Mycobacterium tuberculosis and Mycobacterium paratuberculosis can shift a Th1-dominant response towards a Th0- or a Th2-dominant response as the infection progressed [128, 158]. In bovine tuberculosis, high levels of circulatory IFNγ are detected at the early stage of disease that could inhibit Mycobacterial growth, suggesting that the host most likely mounts an early Th1 response [166, 167, 168]. However, in the chronic tuberculosis increased serum IgG1 (a Th2 associated antibody) is detected in the serum [128]. In line with these observations, in mice and humans, IFNγ expression was upregulated during the early phases of tuberculosis, however, at the chronic phase IL-4 expression was enhanced [169, 170, 171, 172]. Collectively, these results suggest that Mycobacterium tuberculosis can shift an IFNγ (Th1) dominant response towards an IL-4 (Th0 or Th2) dominant response at the later stages of disease. Interestingly, the frequency of antigen-specific Th0 clones was higher in animals showing severe lung pathology than in animals having less severe lesions [128]. Therefore, the authors speculated that Th0 clones may play an important role in skewing the immune response from Th1 (IFNγ) response towards Th0 or Th2 (IL-4) response during the progression of infection (Figure 4) [128]. As in Mycobacterium tuberculosis infections, the immune responses to Mycobacterium paratuberculosis switches from Th1 response to Th2 response while the disease progresses from subclinical to clinical stage [158]. In Mycobacterium paratuberculosis infections, cattle show high levels of IFNγ in the supernatant of cultured PBMCs and high levels of IFNγ mRNA in the intestinal ileal tissues, suggesting an induction of Th1 response against this pathogen [173, 174]. Importantly, cattle clinically infected with Mycobacterium paratuberculosis had significantly lower expression of IFNγ in ileal and caecal lymph nodes compared to cattle at sub-clinical stage of infection [175]. This finding supports the notion that the suppression of the Th1 response at the sub-clinical stage of the disease might have contributed to the progression of disease into the clinical stage. Furthermore, increased antigen-specific IgG1 was detected in animals infected with Mycobacterium paratuberculosis at the clinical stage, suggesting a Th2 response [176, 177]. Together, these findings suggest that the shift of an early-induced Th1-dominant response towards a Th0 or Th2-dominant response is associated with disease progression in both bovine tuberculosis and bovine paratuberculosis.
During the early phases of Respiratory syncytial virus (RSV) infection in humans and mice, the host launches a Th1/Th2 mixed response (i.e., both IFNγ and IL-4), which then shifts towards a Th2 response (i.e., increased circulatory IL-4) during chronic infection [178, 179, 180]. Consistently, cattle infected with Bovine respiratory syncytial virus (BRSV) seem to mount a Th0 response, which turns into a Th2 response during chronic infection [143, 181]. In the past, reports suggested that both IFNγ and IL-4 were detected in the peripheral blood, lymph sample and pulmonary tissues of BRSV infected animals at the early stage, indicating the induction of a Th0 response [144, 181, 182]. Similarly, both IgG1 and IgG2 were detected in the serum, although they peaked at different times during infection [182]. Conversely, IgE and IgG1 levels increased as the infection progressed towards the chronic stage, suggesting a gradual shift from a Th0 towards a Th2 response [143, 181, 182, 183]. Collectively, these studies indicate that these pathogens can switch the early-induced Th0 response towards a Th2 response during chronic infection.
The efficacy of Th0 responses in controlling infections caused by bovine intracellular pathogens is unclear. While Th0 responses seem ineffective against some bovine diseases such as tuberculosis, they can be protective against bovine babesiosis and non-cytopathic Bovine viral diarrhea virus (ncp- BVDV) infection [156, 157, 184]. In Babesiosis, both CD8+ T cell responses and humoral responses appear critical to clear infection. For instance, increased numbers of antigen-specific CD8+ T cells were detected in the peripheral blood of vaccinated animals [156]. Similarly, transferring serum from an immune animal containing both IgG1 and IgG2 can clear infection of sick animals [184]. In this regard, in vitro experiments have demonstrated that the majority of Babesia-specific clones are Th0, which are able to stimulate B cells to produce both IgG1 and IgG2 [22, 138, 184]. Furthermore, IgG1 and IgG2 antibodies were found effective to prevent invasion of bovine erythrocytes by Babesia bovis merozoite in vitro [185]. Collectively, these findings suggest that Th0 responses promote both the cytotoxic activity of CD8+ T cells, and neutralizing activities of IgG subtypes [156].
Cattle might launch different immune responses against different biotypes of the same intracellular pathogen [145, 186, 187]. For instance, while Th0 response was induced against the non-cytopathic (ncp) biotype of Bovine viral diarrhea virus (BVDV), Th1 response was induced during infection caused by the cytopathic biotype (cp) [188]. In experiments with T cells isolated from the ncp-BVDV infected cattle, IL-4 protein in the supernatant of CD4+ T cell culture and IFNγ protein in CD8+ T cell culture were detected, suggesting possible induction of Th0 response [157]. More recently, Palomares et al. analyzed cytokine expression in tracheo-bronchial lymph nodes and found that both IFNγ and IL-4 were detected in ncp-BVDV-infected cattle, but IL-12 mRNA was only detected in cp-BVDV-infected cattle [145]. Additionally, while only IgG2 was detected in the serum of cp-BVDV-infected cattle, both IgG1 and IgG2 were detected in ncp-BVDV infected cattle after day 35 of infection [187]. These results collectively reveal that ncp-BVDV induces a Th0 response whereas cp-BVDV induces a Th1 response in infected cattle.
Thus, available literature supports the notion that cattle launch either Th1 or Th0 responses against most infectious diseases caused by intracellular pathogens (Table 2). Moreover, although further research is required to confirm these findings, the shift from an early Th1 or Th0 response towards a Th2 response is associated with progression of disease towards chronic condition.
Characterization of helper T cell responses in diseases induced by bovine intracellular pathogens. Th1/Th2 cytokines were detected in cultured PBMCs and DLNs; IgG subtype was tested in the serum.
4.2 Most extracellular pathogens induce either a Th2 or Th0 response in cattle
In mice and humans, Th2 responses are typically effective in controlling extracellular pathogens. In this regard, Th2 cytokines can induce processes such as IgG subtype switching and migration of mast and eosinophils to the site of infection that are critical for defending the host against extracellular bacteria and parasites [98]. In cattle, most of extracellular parasites induce either Th2 or Th0 responses [193, 194, 195]. However, some pathogens are capable of suppressing Th2 response, which is associated with the establishment of chronic infections [196].
Generally, Th2 responses are effective in controlling gastrointestinal nematodes such as Cooperia oncophora [197, 198]. Infected animals had increased level of antigen-specific IgG1 (Th2 associated antibody) in the serum [199]. Consistently, a high titer of pathogen specific IgG1 was associated with a better immune response [200]. Similarly, increased numbers of peripheral eosinophils (a Th2 response feature) was associated with increased expulsion of cooperial larvae [200]. Importantly, cytokine analysis of the intestinal tissue of disease resistant cattle demonstrated high expression level of IL-4 and IL-13 mRNA compared to those susceptible animals [201, 202]. These results offer compelling evidence that Th2 response is critical to control infection caused by some extracellular pathogens such as Cooperia oncophora.
Interestingly, some extracellular parasites such as Dictyocaulus viviparus (lung worm) are capable of shifting the initial Th2 or Th0 response into an ineffective Th1 response to establish chronic infections [203, 204]. At the early stage, both IL-4 and IFNγ were detected in the lungs and DLNs after day 15 of lung worm infection, indicating an initial Th0 response [205]. However, subsequent research only detected increased IL-4 mRNA for a short period of time in the Broncho-alveolar lavage fluid (BALF) of infected cattle, suggesting a possible Th2 response [206]. In line with this finding, high level of total IgE (antigen-specific plus non-specific) in the serum and BALF was associated with the clearance of lungworm [203]. Furthermore, in the chronically infected animals the detection of Th1 associated antibody (i.e., IgG2) in the serum, was associated with increased lungworm larval excretion [204]. These data indicate that bovine lungworm might shift the early-induced Th0 or Th2 response towards a Th1 dominant response to establish chronic infection.
In cattle Fasciola hepatica (liver fluke) can modulate the early-induced Th1 or Th0 response into an ineffective Th2 response at the later phases of the disease [207, 208]. Of note, although an initial Th1 response was observed in the peripheral blood, a Th0 response was also observed inside the hepatic lymph node, as indicated by the detection of both IFNγ and IL-4 [209, 210, 211, 212]. Collectively, these experiments suggest that cattle might launch either a Th1 or a Th0 response at the early stages of liver fluke infection. However, at later stages, the response is shifted to a Th2 response as indicated by the significantly increased expression of IL-4 mRNA (x6) and significantly reduced expression of IFNγ mRNA (x6) in the hepatic tissue of infected animals, which is consistent with several other reports [140, 213, 214]. In line with these observations, peripheral blood lymphocytes obtained from chronically infected animals failed to induce IFNγ secretion when co-cultured with adult fluke antigen in vitro [209]. Importantly, chronically infected cattle typically show high levels of antigen-specific IgG1 in the serum [140]. Altogether, these findings suggest that Fasciola hepatica might switch a Th1 or a Th0 dominant response to a Th2 dominant response at the chronic stage of disease.
Ostertagia ostertagi (OO), an economically important abomasal nematode, typically induces Th0 response [215]. Bovine OO usually causes chronic infection and requires long-term repetitive exposure (at least 2 years) to develop effective immunity [216]. Both pathogen-specific IgG subtypes (IgG1 and IgG2) were detected in OO-infected cattle, with higher serum IgG1 titer than IgG2 [217]. Similarly, mRNAs of both IL-4 and IFNγ were upregulated in the abomasal lymph nodes of experimentally infected cattle from day 11 to day 28 after infection, suggesting the induction of a Th0 responses [215]. In contrast to this observation, subsequent research demonstrated induction of Th2 response in the abomasal lymph nodes of OO infected cattle [218]. The differences observed between these two experiments might be explained, at least in part, by the differences in time points for cytokine detection and in the number of L3 larvae used for experimental infection. More specifically, while Canals et al. measured cytokine expression from day 11 to day 28 post infection and used 200,000 L3 larvae for experimental infection, Claerebout (2005) measured cytokine expression after 8 weeks post primary infection and only used 25,000 L3 larvae [215, 219]. Recently, Mihi et al. experimentally infected cattle with 200,000 L3 larvae and tested the gene expression of Th1/Th2 cytokines at different time points; interestingly, the authors observed a positive association between upregulation of both IFNγ and IL-4 (in mucosa) with migration of adult (L5) worms out of gastric gland towards abomasal mucosa [146]. These observations suggest that Ostertagia ostertagi may modulate the bovine immune response by inducing a Th0 response, which is ineffective in controlling OO and leads to the establishment of chronic infections.
Immune response against extracellular pathogens may vary at the systemic and local levels, such as in bovine trichomoniasis, where Th0 response is induced in the serum, and Th2 response in the mucosal secretion [220, 221]. More specifically, Trichomonas foetus upregulates both IgG1 and IgG2 in the serum but only IgG1 in local secretions from cervix, vagina, and uterus [220, 221]. Furthermore, animals immunized with specific antigen of Trichomonas foetus showed resistance to the experimental challenge, which was associated with the upregulation of both antigen-specific IgG1 and IgG2 in the serum [222, 223]. Trichomonas foetus seems to induce a Th0 response in the circulation, but a Th2 response in the mucosa. In addition, the systemic Th0 response may be protective against Trichomonas foetus rechallange.
Generally, Th2 response is effective in controlling extracellular bacteria [224]. For instance, Th2 response controls Clostridium difficile infection in humans and Streptococcus suis infection in pigs [224, 225]. In cattle, only few reports are available on CD4+ T cell response to extracellular bacteria such as E. coli. At this moment, the common understanding is both CD8+ T cell and antibodies seem to be critical to generate protective immunity (consistent with humans) in E. coli 0157:H7 infection [193, 194, 226].
Collectively, the results obtained from multiple experiments indicates that extracellular pathogens typically trigger Th2 or Th0 responses in cattle as shown in Table 3, and some extracellular pathogens modulate initial Th2 or Th0 responses to ineffective Th1 responses that are associated with the development of chronic infection.
Characterization of helper T cell responses in diseases caused by bovine extracellular pathogens. Th1/Th2 cytokines were detected in cultured PBMCs and DLNs; IgG subtype was tested in the serum.
4.3 Pathogens regulate the availability and the strength of three critical signals to suppress effective CD4+ T cell responses
Whenever a pathogen invades and starts multiplying, the host mounts a coordinated attack in order to clear the infection. To counteract the host attacks, some pathogens can interfere with helper T cell responses to establish chronic infections. This can be achieved through unique strategies that impair the availability or strength of the signals required for the activation and differentiation of CD4+ T cells (Figure 1). For example, pathogens such as Salmonella, and Mycobacterium tuberculosis can downregulate MHC-II expression in APC, which diminishes the strength of the 1st signal (antigen stimulation) [233, 234]. In addition, pathogens can reduce the expression of co-stimulatory molecules (2nd signal) and change the type of APCs (e.g. dendritic cell vs. macrophage), which can collectively impair all of the three signals required for the activation and differentiation of T cells (Figure 1) [235, 236].
Bovine pathogens escape from effective CD4+ T cell responses in a very similar way to those of mice and humans. They can regulate the availability, type, and strength of three signals. Some pathogens such as Bovine herpes virus type-1 (BHV-1), Bovine papilloma virus (BPV), and Mycobacterium paratuberculosis can undermine the strength of antigen stimulation (1st signal) by downregulating MHC-I expression, which is actively involved in antigen presentation to CD8+ T cells [237, 238, 239]. Similarly, some pathogens can disrupt the host T cell response through inhibiting the co-stimulatory signals [211, 240, 241]. Co-stimulatory molecules expressed on the surface of CD4+ T cells (as shown in Figure 1) are of two types: one provides activating signals, and the other provides inhibiting signals [242]. Pathogens such as, Bovine leukemia virus, Anaplasma marginale, and Fasciola hepatica can upregulate the expression of inhibitory molecules like program cell death protein-1 (PD-1), which severely impairs the T cell response when these inhibitory molecules bind to their ligands on the surface of APCs [211, 240, 241]. Additionally, pathogens such as Ostertagia ostertagi and Myctobacterium paratuberculosis can induce immune-regulatory cytokines that can inhibit the activation, differentiation, and expansion of effector CD4+ T cell subtypes [26, 243, 244]. More specifically, Ostertagia ostertagi may stimulate neutrophils to produce IL-10, which can suppress bovine CD4+ T cell activation [26]. Furthermore, pathogens like Fasciola hepatica can reduce the number of APCs by apoptosis, which curtails the availability of all activating signals [211]. Moreover, pathogens such as Anaplasma marginale, Bovine herpes virus − 1 and Bovine viral diarrhea virus can directly cause apoptosis of antigen-specific CD4+ T cell and starkly compromise the ability of the host to co-ordinate effective CD8+ T and antibody responses [241, 245, 246, 247]. In short, bovine pathogens regulate the CD4+ T cell responses by reducing the availability and strength of the three activating signals by changing the type and number of APCs, or by interfering with co-stimulation and cytokine production.
4.4 Pathogens regulate the CD4+ T cell differentiation process to establish chronic infections in cattle
In addition to regulating activation signals, during the course of infection, pathogens can also regulate CD4+ T cell differentiation to evade the effective immune response mounted by the host. As already explained, intracellular pathogens can shift effective Th1 response to an ineffective Th2 response; similarly, extracellular pathogens can shift an effective Th2 response to an ineffective Th1 response, in order to promote the chronic infection in the host. For example, S. japonicum in mice can shift a Th2 response to an ineffective Th1 response by triggering apoptosis of Th2 cells via granzyme B signal pathway [248]. Similarly, some authors suggested that in chronic diseases such as bovine tuberculosis, immune complexes circulating in the blood might interfere specifically with Th1 response thus leading to a relatively increased Th2 response [249]. In cattle, intracellular pathogens including Mycobacterium tuberculosis, Mycobacterium paratuberculosis and Bovine respiratory syncytial virus (BRSV) shift the immune responses from a Th1 or a Th0 to an ineffective Th2 response, to establish chronic infections [128, 158]. In the same manner, extracellular pathogens such as Dictyocaulus viviparus modulate the immune response from a Th0 or a Th2 response to an ineffective Th1 response and establish the chronic infection [203, 204]. In summary, a fraction of bovine pathogens can skew the CD4+ T cell polarization to an ineffective subtype that cannot control their infection, which leads to the establishment of chronic infections.
5. Conclusion and future directions
After receiving three stimulation signals from APCs, naïve CD4+ T cells differentiate into effector subtypes such as Th1, Th2, and Th0 cells. While clear-cut Th1 and Th2 are the common subtypes detected in mice and humans, hybrid Th0 is common in cattle infected by both intracellular and extracellular pathogens. In fact, Th0 responses induced in many bovine diseases might consist of a mixed population of Th1, Th2, and Th0 subtypes. Thus, despite similarities in general, bovine CD4+ T cell responses seem to be partially different from the Th1/Th2 responses classically defined in mice and humans. Therefore, understanding the mechanisms of bovine CD4+ T cell differentiation and its regulation by pathogens may facilitate the development of more effective vaccines and designing immune intervention strategies against important chronic bovine infectious diseases.
Acknowledgments
We gratefully acknowledge the Grant 2016-67015-24948 (to Z.X.) and Grant 2019-67015-29831 (to Z.X.), the Jorgensen Foundation (to Z.X.), and MAES program in University of Maryland (to Z.X.). The figures were created with BioRender.com.
Conflict of interest
The authors state no conflict of interests.
\n',keywords:"bovine, CD4+ T cell differentiation, antigen-specific clones, Th0 responses, pathogens, chronic infections",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/78918.pdf",chapterXML:"https://mts.intechopen.com/source/xml/78918.xml",downloadPdfUrl:"/chapter/pdf-download/78918",previewPdfUrl:"/chapter/pdf-preview/78918",totalDownloads:116,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 18th 2021",dateReviewed:"September 10th 2021",datePrePublished:"October 22nd 2021",datePublished:"February 23rd 2022",dateFinished:"October 9th 2021",readingETA:"0",abstract:"Helper CD4+ T cells are essential in shaping effective antibody response and cytotoxic T cell response against pathogen invasion. There are two subtypes of pathogen-specific helper T cells in mice and humans; type 1 (Th1) and type 2 (Th2), with Th1 producing interferon-gamma (IFNγ) and Th2 producing interleukin-4 (IL-4). While effective Th1 controls intracellular pathogens like viruses, efficient Th2 controls extracellular pathogens like most parasites. However, the most predominant CD4+ T cell subtype in cattle is Th0, which produces both IFNγ and IL-4, and only exists in small amounts in mice and humans. Moreover, in many bovine infections, both IFNγ and IL-4 were detected in the blood and both antigen-specific IgG2 (Th1 associated bovine antibody) and antigen-specific IgG1 (Th2 associated bovine antibody) were upregulated in the serum, suggesting bovine CD4+ T cell responses may vary from those in mice and humans. How bovine CD4+ T cell differentiation differs from that in mice and humans and how some critical bovine pathogens regulate immunity to establish chronic infections are largely unknown. This chapter summarizes current literature and identifies the knowledge gaps to provide insights into future research in the field.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/78918",risUrl:"/chapter/ris/78918",signatures:"Anmol Kandel, Magdalena Masello and Zhengguo Xiao",book:{id:"10751",type:"book",title:"Bovine Science",subtitle:"Challenges and Advances",fullTitle:"Bovine Science - Challenges and Advances",slug:"bovine-science-challenges-and-advances",publishedDate:"February 23rd 2022",bookSignature:"Muhammad Abubakar",coverURL:"https://cdn.intechopen.com/books/images_new/10751.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-509-4",printIsbn:"978-1-83969-508-7",pdfIsbn:"978-1-83969-510-0",isAvailableForWebshopOrdering:!0,editors:[{id:"112070",title:"Dr.",name:"Muhammad",middleName:null,surname:"Abubakar",slug:"muhammad-abubakar",fullName:"Muhammad Abubakar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"351149",title:"Prof.",name:"Zhengguo",middleName:null,surname:"Xiao",fullName:"Zhengguo Xiao",slug:"zhengguo-xiao",email:"xiao0028@umd.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"351664",title:"Mr.",name:"Anmol",middleName:null,surname:"Kandel",fullName:"Anmol Kandel",slug:"anmol-kandel",email:"akandel1@umd.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Maryland, College Park",institutionURL:null,country:{name:"United States of America"}}},{id:"351665",title:"Dr.",name:"Magdalena",middleName:null,surname:"Masello",fullName:"Magdalena Masello",slug:"magdalena-masello",email:"mmasello@umd.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Maryland, College Park",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. CD4+ T cells regulate adaptive immunity",level:"1"},{id:"sec_2_2",title:"2.1 Th1 cells coordinate CD8+ T cell response to intracellular pathogens",level:"2"},{id:"sec_2_3",title:"2.2 Differentiated Th2 cells coordinate humoral response against extracellular pathogens",level:"3"},{id:"sec_4_2",title:"2.3 Th1/Th2 cytokines induce immunoglobulin class switching during infection",level:"2"},{id:"sec_5_2",title:"2.4 Cytokines and transcription factors mediate Th1/Th2 cross-regulation",level:"2"},{id:"sec_6_2",title:"2.5 Distinct Th1 and Th2 are the most dominant antigen-specific clones in mice and humans",level:"2"},{id:"sec_7_2",title:"2.6 Th0 is the most dominant antigen-specific clone in cattle",level:"2"},{id:"sec_9",title:"3. Many critical bovine pathogens induce Th0 responses",level:"1"},{id:"sec_10",title:"4. Advancement of technology facilitates the progress in bovine immunology",level:"1"},{id:"sec_10_2",title:"4.1 Most intracellular pathogens induce either a Th1 or Th0 response in cattle",level:"2"},{id:"sec_11_2",title:"4.2 Most extracellular pathogens induce either a Th2 or Th0 response in cattle",level:"2"},{id:"sec_12_2",title:"4.3 Pathogens regulate the availability and the strength of three critical signals to suppress effective CD4+ T cell responses",level:"2"},{id:"sec_13_2",title:"4.4 Pathogens regulate the CD4+ T cell differentiation process to establish chronic infections in cattle",level:"2"},{id:"sec_15",title:"5. Conclusion and future directions",level:"1"},{id:"sec_16",title:"Acknowledgments",level:"1"},{id:"sec_19",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Mosmann TR, Fowell DJ. The Th1/Th2 paradigm in infections. Immunology of infectious diseases. 2001:161-174'},{id:"B2",body:'Zhu J, Paul WE. 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Cell. 1995;80(5):707-718'},{id:"B236",body:'Sallusto F, Lanzavecchia A. The instructive role of dendritic cells on T-cell responses. Arthritis Research & Therapy. 2002;4(3):1-6'},{id:"B237",body:'Nataraj C, Eidmann S, Hariharan MJ, Sur JH, Perry GA, Srikumaran S. Bovine herpesvirus 1 downregulates the expression of bovine MHC class I molecules. Viral immunology. 1997;10(1):21-34'},{id:"B238",body:'Araibi EH, Marchetti B, Ashrafi GH, Campo MS. Downregulation of major histocompatibility complex class I in bovine papillomas. The Journal of general virology. 2004;85(Pt 10):2809-2814'},{id:"B239",body:'Weiss DJ, Evanson OA, McClenahan DJ, Abrahamsen MS, Walcheck BK. Regulation of Expression of Major Histocompatibility Antigens by Bovine Macrophages Infected withMycobacterium avium subsp. paratuberculosis orMycobacterium avium subsp. avium. Infection and immunity. 2001;69(2):1002-1008'},{id:"B240",body:'Okagawa T, Konnai S, Deringer JR, Ueti MW, Scoles GA, Murata S, et al. Cooperation of PD-1 and LAG-3 contributes to T-cell exhaustion in Anaplasma marginale-infected cattle. Infection and immunity. 2016;84(10):2779-2790'},{id:"B241",body:'Okagawa T, Konnai S, Nishimori A, Maekawa N, Goto S, Ikebuchi R, et al. Cooperation of PD-1 and LAG-3 in the exhaustion of CD4+ and CD8+ T cells during bovine leukemia virus infection. Veterinary research. 2018;49(1):1-12'},{id:"B242",body:'Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology. 2013;13(4):227-242'},{id:"B243",body:'de Almeida DE, Colvin CJ, Coussens PM. Antigen-specific regulatory T cells in bovine paratuberculosis. Veterinary immunology and immunopathology. 2008;125(3-4):234-245'},{id:"B244",body:'Sheridan MP, Browne JA, Doyle MB, Fitzsimons T, McGill K, Gormley E. IL-10 suppression of IFN-γ responses in tuberculin-stimulated whole blood from Mycobacterium bovis infected cattle. Vet Immunol Immunopathol. 2017;189:36-42'},{id:"B245",body:'Eskra L, Splitter GA. Bovine herpesvirus-1 infects activated CD4+ lymphocytes. Journal of general Virology. 1997;78(9):2159-2166'},{id:"B246",body:'Chase C, Elmowalid G, Yousif A. The immune response to bovine viral diarrhea virus: a constantly changing picture. The Veterinary clinics of North America Food animal practice. 2004;20(1):95-114'},{id:"B247",body:'Han S, Norimine J, Palmer GH, Mwangi W, Lahmers KK, Brown WC. Rapid deletion of antigen-specific CD4+ T cells following infection represents a strategy of immune evasion and persistence for Anaplasma marginale. The Journal of Immunology. 2008;181(11):7759-7769'},{id:"B248",body:'Xu X, Wen X, Chi Y, He L, Zhou S, Wang X, et al. Activation-induced T helper cell death contributes to Th1/Th2 polarization following murine Schistosoma japonicum infection. Journal of Biomedicine and Biotechnology. 2010;2010'},{id:"B249",body:'Berger S, Ballo H, Stutte H. 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Virginia Polytechnic Institute and State University
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CSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
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The Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
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The University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
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\n\t
Virginia Polytechnic Institute and State University
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