Visceral leishmaniasis: species, region of occurrence, vectors, reservoirs, and mammal hosts.
\r\n\tThe study of populations and plant communities in their different aspects; ecological, structural, functional and dynamic, it is essential to establish a posteriori models of forest and agricultural management.
\r\n\r\n\tFor this, the methodological approaches on the type of sampling are considered essential, since there are differences between the purely ecological and the phytosociological methods, despite the fact that both pursue the same objective.
\r\n\tAlthough the ecological method for the knowledge of the vegetation is widely extended, the phytosociological one is no less so, since in the European Union it has been developed as a consequence of policies on sustainability, through which regulations have been issued, such as the habitats directive.
\r\n\tOn the other hand, research on plant dynamics and knowledge of the landscape in an integral way, have multiplied in the last 30 years, which has favored a deep knowledge of the floristic and phytocenotic wealth, which is fundamental for agricultural management, livestock and forestry.
",isbn:"978-1-83969-386-1",printIsbn:"978-1-83969-385-4",pdfIsbn:"978-1-83969-387-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"0abf2a59ee63fc1ba4fb64d77c9b1be7",bookSignature:"Dr. Eusebio Cano Carmona, Dr. Ricardo Quinto Canas, Dr. Ana Cano Ortiz and Dr. Carmelo Maria Musarella",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9662.jpg",keywords:"Climatic Factors, Bioclimate, Thermotype, Flora, Conservation, Phytocenosis, Plant Dynamics, Landscape, Cartography, Vegetation Series, Crops, Reforestation",numberOfDownloads:55,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2020",dateEndSecondStepPublish:"January 25th 2021",dateEndThirdStepPublish:"March 26th 2021",dateEndFourthStepPublish:"June 14th 2021",dateEndFifthStepPublish:"August 13th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Cano Carmona and colleagues have directed 12 doctoral theses and more than 200 publications among articles, books, and book chapters. He has participated in national and international congresses with about 250 papers. He has held a number of different academic positions, including Dean of the Faculty of Experimental Sciences at the University of Jaen, Spain, and founder and director of the International Seminar on Management and Conservation of Biodiversity.",coeditorOneBiosketch:"Ricardo Jorge Quinto Canas is currently an Invited Assistant Professor in the Faculty of Sciences and Technology at the University of Algarve – Portugal, and a member of the Centre of Marine Sciences (CCMAR), University of Algarve. His current research projects focus on Botany, Vegetation Science (Geobotany), Biogeography, Plant Ecology, and Biology Conservation, aiming to support Nature Conservation.",coeditorTwoBiosketch:"Ana Cano Ortiz's fundamental line of research is related to botanical bioindicators. She has worked in Spain, Italy, Portugal, and Central America. It presents more than one hundred works published in various national and international journals, as well as books and book chapters; and has presented a hundred papers to national and international congresses.",coeditorThreeBiosketch:"Carmelo Maria Musarella is a biologist, specialized in Plant Biology. He is a member of the permanent scientific committee of the International Seminar on “Biodiversity Conservation and Management” guested by several European universities. He has participated in several international and national congresses, seminars, and workshops and presented oral communications and posters.",coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"87846",title:"Dr.",name:"Eusebio",middleName:null,surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona",profilePictureURL:"https://mts.intechopen.com/storage/users/87846/images/system/87846.png",biography:"Eusebio Cano Carmona obtained a PhD in Sciences from the\nUniversity of Granada, Spain. He is Professor of Botany at the\nUniversity of Jaén, Spain. His focus is flora and vegetation and he\nhas conducted research in Spain, Italy, Portugal, Palestine, the\nCaribbean islands and Mexico. As a result of these investigations,\nDr. Cano Carmona and colleagues have directed 12 doctoral theses\nand more than 200 publications among articles, books and book\nchapters. He has participated in national and international congresses with about\n250 papers/communications. He has held a number of different academic positions,\nincluding Dean of the Faculty of Experimental Sciences at the University of Jaen,\nSpain and founder and director of the International Seminar on Management and\nConservation of Biodiversity, a position he has held for 13 years. He is also a member of the Spanish, Portuguese and Italian societies of Geobotany.",institutionString:"University of Jaén",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Jaén",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"216982",title:"Dr.",name:"Ricardo Quinto",middleName:null,surname:"Canas",slug:"ricardo-quinto-canas",fullName:"Ricardo Quinto Canas",profilePictureURL:"https://mts.intechopen.com/storage/users/216982/images/system/216982.JPG",biography:"Ricardo Quinto Canas, Phd in Analysis and Management of Ecosystems, is currently an Invited Assistant Professor in the Faculty\nof Sciences and Technology at the University of Algarve, Portugal, and member of the Centre of Marine Sciences (CCMAR),\nUniversity of Algarve. He is also the Head of Division of Environmental Impact Assessment - Algarve Regional Coordination\nand Development Commission (CCDR - Algarve). 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Her research focus is related to botanical bioindicators.\nDr. Ortiz has worked in Spain, Italy, Portugal and Central America. She has published more than 100 works in various national\nand international journals, as well as books and book chapters.\nShe has also presented a great number of papers/communications to national and\ninternational congresses.",institutionString:"University of Jaén",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Jaén",institutionURL:null,country:{name:"Spain"}}},coeditorThree:{id:"276295",title:"Dr.",name:"Carmelo Maria",middleName:null,surname:"Musarella",slug:"carmelo-maria-musarella",fullName:"Carmelo Maria Musarella",profilePictureURL:"https://mts.intechopen.com/storage/users/276295/images/system/276295.jpg",biography:"Carmelo Maria Musarella, PhD (Reggio Calabria, Italy –\n23/01/1975) is a biologist, specializing in plant biology. He\nstudied and worked in several European Universities: Messina,\nCatania, Reggio Calabria, Rome (Italy), Valencia, Jaén, Almeria\n(Spain), and Evora (Portugal). He was the Adjunct Professor\nof Plant Biology at the “Mediterranea” University of Reggio\nCalabria (Italy). His research topics are: floristic, vegetation,\nhabitat, biogeography, taxonomy, ethnobotany, endemisms, alien species, and\nbiodiversity conservation. He has authored many research articles published in\nindexed journals and books. He has been the guest editor for Plant Biosystems and a\nreferee for this same journal and others. He is a member of the permanent scientific\ncommittee of International Seminar on “Biodiversity Conservation and Management”, which includes several European universities. 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More than 20 parasite species are involved in the three different clinical manifestation diseases in human beings: cutaneous leishmaniasis, mucosal leishmaniasis, and visceral leishmaniasis (kala-azar). Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis in a patient who has recovered from the disease. The vectors are sand flies, insects of medical and veterinary relevance, and different species involved in its transmission.
\nAccording to Pan American Health Organization (PAHO) and World Health Organization (WHO), there are more than 12 million people infected with leishmaniasis, and 350 million are at risk in the world. Cutaneous leishmaniases are concentrated in ten countries, four of which are in the Americas: Brazil, Colombia, Peru, and Nicaragua. Ninety percent of visceral leishmaniasis cases occur in Brazil, Ethiopia, India, Bangladesh, Sudan, and South Sudan. In the Americas, an average 60,000 cases of cutaneous and mucosal leishmaniasis and 4000 cases of visceral leishmaniasis are diagnosed annually, with a fatality rate of 7% (Figure 1) [1].
\nHigh-burden countries for both visceral and cutaneous leishmaniasis [
The aim of this chapter is to describe the main aspects of canine visceral leishmaniasis (CVL) with emphasis in Brazil.
\nVisceral leishmaniasis (VL), also known as kala-azar, is a disease caused by an obligate intracellular protozoon belonging to the family Trypanosomatidae, genus
World distribution of human visceral leishmaniasis, 2013 [
Species | \nRegion | \nVector | \nHost/reservoir | \n
---|---|---|---|
\n | \nOld World: Europe Asia Africa | \n\n \n | \nHumans Dogs Wild canids | \n
\n | \nOld World: Asia Africa | \n\n \n | \nHumans | \n
New World: South, Central, and North America | \nHumans Dogs Wild canids Felines Marsupials | \n
The life cycle of
Transmission occurs when the infected vector does a new blood meal and inoculates the infective form of
VL vectors belong to the order Diptera, family Psychodidae, subfamily Phlebotominae, genus
Sand flies are small-sized, light brown-colored insects, with a coat of hair over their body. They measure between 2 and 3 mm [11]. Their flight range reaches about 150–300 m (diameter of 300–600 m), but may be longer depending on the species. They usually fly in small jumps and have crepuscular and nocturnal activity [12].
\nHematophagy is a unique habit of females, who require blood for ovary maturation. Hence, they are able to transmit the disease. When females feed on blood, they hold their wings upright. A variety of animals has been identified as dietary hosts of sand flies, which have very eclectic feeding habits. Females lay eggs in moist soil, rich in organic matter [13].
\nVL caused by
Leishmaniasis starts from the wild cycle, involving reservoirs such as wild canids and marsupials. As for the domestic cycle, the main reservoir is the domestic dog (Canis lupus familiaris) [7]. The link between wild and domestic cycles occurs when humans install dwellings on forest banks [14] and, most likely, because some wild reservoirs have synanthropic habits (Figure 3) [15].
\nCanine visceral leishmaniasis (CVL) is crucial from an epidemiological point of view, as it is more prevalent than human VL. Dogs exhibit high levels of subcutaneous parasites and high sensitivity to vectorial infection [12]. Additionally, between 50 and 60% of infected animals are asymptomatic [16]. It is estimated that three out of five asymptomatic positive dogs transmit the parasite to sand flies, and this transmission rate does not significantly change among symptomatic and asymptomatic groups of animals [17].
\nOther animals have been pointed as possible reservoirs, such as rodents [14] and cats, or accidental hosts, such as horses [18]. Adaptation of vectors to different animal species would be a favorable factor for VL transmission [19].
\nEco-epidemiology of visceral leishmaniasis in Pará, Brazil
There are other transmission forms of less epidemiological importance, such as blood transfusion and venereal transmission, apart from vertical transmission, which can be transplacental or transmammary [20–23]. Direct dog-to-dog transmission through bites or wounds has been suggested as responsible for sporadic CVL transmission as well [24, 25].
\nIn recent years, endemic regions have widened, and there has been a sharp increase in number of recorded cases of the disease. Still, it is believed that the impact of leishmaniasis on public health has been underestimated, since its notification is only mandatory in 32 of the 88 affected countries [2]. CVL is endemic in over 70 countries and occurs mainly in the Mediterranean region and South America [26]. Moreno and Alvar concluded that at least 2.5 million dogs are infected in only four countries in Southeastern portion of Western Europe, representing 16.7% of the canine population [27].
\nFranco et al. [28] developed a database of publications on the prevalence of LVC in Europe between the years 1971 and 2006. They found an overall prevalence of 23.2% and average of 10%, the highest taking place in Italy (17.7%), followed by France (8%), Portugal (7.3%), and Spain (5.9%) [28]. In another study, in 18 Portuguese cities with 3974 dogs, the overall prevalence of CVL was of 6.31% and ranged from 0.88% to 16.16% among cities, with high prevalence in inland regions [29].
\nIn Croatia, seroprevalence of CVL ranges from 0 to 42.85% depending on the studied region [30]. In Cyprus, the seroprevalence of the disease in dogs had a ninefold increase compared to 10 years before, reaching 14.9% in 2010 [31]. The average seropositivity of dogs in Greece is 22.1%, and positive animals were found in 43 of 54 cities [32].
\nSeroprevalence of CVL in Southern Europe ranges from less than 5% to over 50% depending on the geographic region [33]. However, the prevalence of infection is significantly higher than both seroprevalence and apparent disease, due to sensitivity of serological techniques and because clinical signs usually only appear in less than half of the population, as in all endemic areas of the world [34].
\nRecent expansion to areas not previously endemic has been recorded in some parts of Europe, as northern Italy [35], in Germany [36], and in northern Spain [37]. The expansion of the CVL is associated with adjacent territories and often with global warming, which favors vector transmission, or with import of infected dogs to non-endemic areas, such as the United Kingdom and Poland [26, 33].
\nIn Africa, VL transmission areas are located near forests [12]. Most of the information published in Africa have often been reports of human cases during epidemic situations, but information on the reservoirs are scarce [38]. In Algeria, the number of cases of CVL is on the rise, with a frequency of 35%, with 25% of positive dogs being asymptomatic [39]. Coastal regions of Northern Morocco are known to be endemic for canine and human VL. Moreover, several cases of CVL caused by
CVL exists in some Asian countries. It is endemic in Iran, with an average prevalence of 14.2%, and variations according to the region: 18.2% in northeast, 12.3% in the central region, and 4.4% in Southeastern Iran [41]. Another study, restricted to southwestern Iran, found a prevalence of 15.4% [42]. In China, VL is an anthropozoonosis which completes its life cycle in dogs, raccoons, coatis, and children [12]. The presence of
CVL has been expanding over the Americas. It currently occurs from southern Canada [45] and the United States [46, 47] to northern Argentina [48, 49]. In North America, it was first reported on hunting kennels of Foxhound dogs in New York, in 1999 [46]. Since then, CVL has been spreading and has so far been diagnosed in 18 North American and two Canadian states, totaling 58 kennels with positive Foxhounds, but with no reports of human cases. Isozyme characterization showed that the isolated agents from 46 Foxhounds are
There are few studies on CVL in Mexico, but human VL cases are constant. Rosete-Ortíz et al. analyzed skin lesions of 25 dogs by immunohistochemistry and PCR in a region where
In Latin America, VL occurs in 12 countries, with 90% of cases concentrated in Brazil [11], distributed in all states of the Northeastern, Midwestern, and Southeastern regions, plus in Roraima, Tocantins, and Pará states, in the Northern region [14]. Among Brazilian cities and states, variation in prevalence of CVL is huge, ranging from 0.7% in Salvador, in the state of Bahia [52], to 51.6% in São Luis Island, Maranhão state [53], both in Northeast, where the disease is most prevalent.
\nCVL urbanization correlates with increasing global mobility [54] associated with demographic and ecological factors. In Latin America, especially in Brazil, Colombia, and Venezuela, migration and urbanization have contributed to the increase in American VL. In Brazil, one example is the rural exodus from the Northeast fields, causing thousands of people to migrate to cities like Fortaleza, Jacobina, João Pessoa, Natal, Petrolina, St. Louis, Sobral, Teresina, and Salvador. They then proceed to live in suburban areas with unsanitary conditions and malnutrition. Migrants often bring along their dogs and raise chicken and pigs around their homes, all ultimately serving as a feed source for the vector. According to Moreno et al., in urban areas, some factors favor the spread of
The state of Rio Grande do Sul, Brazil, was considered CVL-free until 2008, when a case of an autochthonous canine was reported in São Borja [57]. In the same year,
Prevalence of CVL in the world varies widely, and such variation also applies to different locations within the same city, suggesting that different ecosystems favor maintenance of vectors in different manners [60]. As noted by Azevedo et al. [61] and Belo et al. [62], results of studies on prevalence are influenced by various factors such as the region and population studied, the diagnostic method, as well as the sample used.
\nMigration of humans and their pets, disorderly occupation, poor living conditions, deforestation, and climate change associated with vector-adaptive capacity are some of the causes of the global urbanization of leishmaniasis [54].
\nThe best example of the phenomenon of urbanization of zoonotic visceral leishmaniasis is happening in Brazil [54, 63]. VL has invaded urban centers and large capitals with no previous record of autochthonous cases [12]. Epidemiological data show the suburbanization and urbanization of visceral leishmaniasis, highlighting the outbreaks in Rio de Janeiro (RJ), Belo Horizonte (MG), Aracatuba (SP), Santarém (PA), Corumbá (MS), Teresina (PI), Natal (RN), São Luís (MA), Fortaleza (CE), Camaçari (BA), and more recently, occurrence of epidemics in the municipalities of Três Lagoas (MS), Campo Grande (MS), and Palmas (TO) [11].
\nThe prevalence of human VL caused by
There is no consensus on the risk factors associated with CVL, as results differ between the studied Brazilian regions and between countries.
\nIn Croatia, risk factors were sex (male), age (the two most prevalent groups comprise dogs between 3 and 4 years old and between 6 and 7 years old), and location (dogs in some cities are more likely to acquire the disease) [30]. In Spain, seroprevalence was also found to have bimodal age distribution, but the age groups were between 1 and 2 years and between 7 and 8 years; infection is also related to outdoor rearing [64]. In Portugal, risk factors are outdoor rearing, age (over two years), short fur, pure breeds, and location (dogs in the hinterlands are more likely to be affected) [29].
\nIn Brazil, Belo et al. [62] conducted a systematic review of the literature on risk factors associated with CVL, and the variables that showed significant association with infection were short hair, pure breed, rearing restricted to house surroundings, and the presence of green areas adjacent to the house. The occurrence of CVL was also associated with the presence of poultry in domestic environment, free-living dogs, sex (male), and age greater than 1 or 2 years, although these associations were not statistically significant [62].
\nAnother study in Brazil defined risk factors as outdoor rearing, contact with poultry, dogs living in rural areas, the presence of organic matter, the absence of environmental management, and proximity to forests [65]. As for dogs in the countryside, in an endemic area of Northeastern Brazil, the only identified risk factor found was sex, as male dogs were twice as likely to develop the disease [66].
\nThe components of the immune system act in a complex and coordinated manner to prevent entry and survival of foreign agents in the body. The first line of defense is the innate immunity, which responds immediately and unspecifically to a range of pathogens, and further presents them to the constituents of adaptive immunity when needed. Adaptive immunity will then generate a specific response and develop memory cells against such antigen. Performance of these defense mechanisms can control infection and ensure the least possible damage to host tissues.
\nIn visceral leishmaniasis, the result of the relationship between parasite and host is determined by complex factors involving saliva components of the vector insect, agent-secreted surface proteins, and different responses produced by the host [67]. Leishmaniasis can be considered an immune-mediated disease, considering the parasite’s ability to alter the immune system [68]. It ultimately promotes inhibition of immune response by either stimulating the development of regulatory T cells [69] or exerting some degree of control over the complement system, exploring its opsonic properties to facilitate adherence with phagocytic cells and preventing their lytic effects through the action of gp63 glycoprotein expressed on the parasite surface [70]. Thus, infection outcome depends on the parasite’s capacity of developing evasion mechanisms to escape from host responses and remain unharmed in the cytoplasm of phagocytic cells.
\nIt has been documented that resistance to infection by
Through antigen presentation, the cells of innate immunity stimulate the acquired response. Antigen-presenting cells have receptors that recognize pathogen-associated molecular patterns (PAMPs) expressed by the parasite. Among these, the Toll-like receptor (TLR) is one of the most studied. Stimulation of these receptors culminates with the activation of signaling pathways in infected cells, which results in induction of antimicrobial genes and inflammatory cytokines (IL-12, TNF) while increasing the ability of cells to present antigen. Thus, pathogen recognition by TLR receptors helps conducting adaptive immune response against the presented antigen [77].
\nExpression of TLR genes in dogs infected with
Studies have shown that both inlet and survival of
The main effector mechanism involved in protective immune response against
The major subpopulations of lymphocytes are CD4+ T cells (Th1, producing IFN-γ and TNF-α; Th2, secreting IL-4, IL-5, and IL-13; and Th17, producing IL-17 and IL-22) and CD8+ T cells. Antigen-presenting cells submit
The role of CD4+ T cells in the response to visceral leishmaniasis (VL) has not been fully elucidated. Research carried out so far points to a mixed response (Th1/Th2) during infection [84, 85]. It is reported, however, that control of infection depends on Th1 cells that activate macrophages, promoting elimination of intracellular parasites [86], whereas Th2 cells direct the immune system toward humoral response and negatively regulate cellular immunity, promoting Th1 cell anergy [87].
\nCD8+ cells constitute a significant population in cellular immunity against canine visceral leishmaniasis (CVL), outnumbering CD4+ cells in the dermis [87]. They play an important role in resistance to infection. Guerra et al. [88] associated phenotypic changes with tissue parasitism in the spleen and skin of infected dogs. They noticed that the high frequency of CD8+-circulating lymphocytes is directly related to low splenic parasitism and that there is a negative correlation between CD8+ T cells with skin parasite density, indicating that this cell type relates to resistance against LVC [88].
\nThe regulatory role of FOXP3+ CD4+ T cells in canine VL has not been fully elucidated; however, reduction of Treg cell percentage in peripheral blood of infected dogs has been observed [89]. Silva et al. [90] reported increased production of IL-10 by splenic Treg cells of dogs with LV, along with decrease in the total number of T cells when compared to healthy dogs. The findings suggest that Treg cells are a major source of IL-10 in the spleen and participate in the modulation of immune response, while a small percentage of these cells in infected dogs may be related to persistent immune activation [90].
\nT-cell exhaustion (CD4+ and CD8+ cells) in peripheral blood of dogs with LV, followed by reduction of the expression of cytokines (such as IFN-γ), was recently demonstrated. This phenomenon, called cell exhaustion, is mainly mediated by high expression of programmed death protein (“programmed cell death 1,” PD-1) and may be related to the strong immunosuppression observed in advanced stages of the disease, corresponding to increase in symptomatology of VL [86].
\nThe role of B cells in CVL is unclear. However, increases in CD21+ B cell, CD4+ T cell, and CD8+ T cell levels are frequently reported, as for the clinical asymptomatic form. Lower frequency of B cells and monocytes in the bloodstream is an important marker of severe disease, while increased levels of CD8 + T cells appear to be the most important phenotypic feature for asymptomatic clinical presentation [74]. Among symptomatic animals, decrease in CD21+ B-cell count associates with decreased CD4+ T cells, which does not occur with asymptomatic or disease-free control animals, suggesting that the decay of immunity in leishmaniasis may be related to decrease in the CD4+ T-cell population [91].
\nAlthough the relationship between a pattern of anti-
Cytokine patterns for CVL have not been well established. Studies are inconclusive, so the pattern of immune response associated with resistance or susceptibility in infected animals is yet to be established.
\nOne of the first studies on cytokine profiling in CVL was performed by Pinelli et al. [71], who observed high levels of IL-2 and tumor necrosis factor alpha (TNF-α) in asymptomatic dogs, compared with symptomatic ones, which suggests a role of these cytokines in resistance to
Profile of cytokines in peripheral blood mononuclear cells (PBMC) culture from asymptomatic dogs experimentally infected with
After evaluating expression of cytokines in spleen cells from dogs naturally infected with
Souza [99] states that asymptomatic dogs have low dermal parasitism and exhibit a mixed pattern of immune response, with simultaneous increase of type I (IFN-γ and TNF-α) and type II (IL-5 and IL-13) cytokines, but predominance of type I response. According to the author, increased and simultaneous expression of IFN-γ and TNF-α in the skin of infected dogs enables the speculation that these mediators are closely involved with protection mechanisms during CVL, since these cytokines increased in the skin of animals with the asymptomatic clinical form. Increased expression of IL-5 and IL-13 in the skin of healthy dogs and negative correlation of the latter with clinical disease progression were also observed. Furthermore, high simultaneous expression of IFN-γ and IL-13 was found in asymptomatic dogs, indicating the role of IL-13 in establishing milder clinical forms [99].
\nRegarding cytokine profile in the bone marrow, Quinnell et al. [94] reported that expression of mRNA for IL-10, IL-4, and IL-18 was not elevated in infected dogs. However, some infected dogs had detectable expression of mRNA for IL-4 significantly correlated with more severe clinical signs. Moreover, expression of mRNA for IL-13 was not detected either in control or in infected dogs, and unlike in human infection, immunosuppressive activity of IL-10 was not observed in CVL [94].
\nDogs infected with
Another subject lacking clarification is the participation of chemokines and their receptors in resistance or susceptibility to LVC. Knowledge surrounding the role of these modulators in response to
Menezes-Souza et al. [101] analyzed the expression of CCL2, CCl4, CCL5, CCL13, CCL17, CCL21, CCL24, and CXCL8 chemokines in the skin of 35 dogs naturally infected by
After connecting clinical findings in naturally infected dogs with liver and spleen parasitism and expression levels for cytokines, chemokines, and their receptors, Albuquerque [67] showed that symptomatic dogs exhibit low expression of these modulators, alongside lower inflammatory response, and higher parasite load—primarily in the liver—than asymptomatic animals. CXCL10 was the only chemokine found at a much higher concentration in both the liver and the spleen of symptomatic animals. It also positively correlated with clinical score. The author indicates that expression profiles of hepatic and splenic chemokines and their receptors are essential for induction of correct cell inflammatory profile, as it has potential to contain the infection and the disease. Impaired cell migration facilitates replication of the parasite and development of CVL symptoms [67].
\nUnderstanding of the immune response in canine visceral leishmaniasis may reveal the factors involved with the onset and severity of clinical signs and the damage to host tissues. Additionally, it takes place as an indispensable tool for development of an effective vaccine.
\nClassical symptomatic case with emaciation, thickened skin, cutaneous lesions, exfoliative dermatitis, fur loss, and cutaneous ulcers.
Canine visceral leishmaniasis presents a clinical picture ranging from asymptomatic to classical symptomatic cases (Figure 4). Infected animals without clinical signs comprise an alarming 40–80% of all cases, for asymptomatic dogs are a major source of infection for sand flies, and owners naturally resist to elimination of their animals [102].
\nAt first, kala-azar signals can be rather discrete and easily confused with other diseases. Animals may have discrete lesions on the edge of the ears and slight changes in blood profile (mild anemia and/or thrombocytopenia).
\nClinical leishmaniasis may appear quickly after infection or within two years. Classic canine kala-azar is characterized by thickened skin, cutaneous lesions, intermittent fever, appearance shift and fur loss, periorbital alopecia, hepatosplenomegaly, akinesia, diarrhea, onychogryphosis (nail growth; Figure 5), and nosebleeding. Partial paralysis of hindquarters is often seen in the final stage of the disease.
\nOnychogryphosis.
The most common skin lesions in dogs with kala-azar are exfoliative dermatitis (generalized, regional, or localized); ulcerative dermatitis, onychogryphosis, and papular dermatitis.
\nCutaneous ulcers are usually located on the ear margins and have been attributed to local trauma and/or vasculitis, pressure points (Figure 6), limbs, and mucocutaneous junctions. Focal or multifocal nodular forms have a high amastigote load and may indicate either inefficient or strong cellular immunity by the host [101, 103–105].
\nOcular disease occurs in CVL, with anterior uveitis being the most common ocular manifestation, characterized by conjunctivitis, blepharitis, periocular alopecia, exophthalmia, keratitis, keratoconjunctivitis sicca, anterior uveitis, glaucoma, and retinal detachment [106].
\nThe nosebleeding (epistaxis) occurs due to thrombocytopenia and is often confused with ehrlichiosis, a bacterial disease transmitted by ticks, which in many cases might associate with leishmaniasis. In endemic areas, it is advisable that any diagnosis of ehrlichia or anaplasma in dogs must be accompanied by differential diagnosis of kala-azar.
\nIn general, dogs in endemic areas are poly-infected and malnourished, particularly stray dogs or those who frequently wander on the streets, leading to a plurality of overlapping clinical pictures. Among other conditions, furfuraceous flaking due to scabies, weight loss as consequence of other infections or lymphomas, and autoimmune diseases, such as systemic lupus erythematosus, often confuse diagnosis since clinical signs are usually not pathognomonic. Therefore, differential diagnosis must be a concern for the small animal clinician [107, 108].
\nCutaneous ulcer located on a pressure point.
Treating seropositive dogs for canine visceral leishmaniasis (CVL) is a controversial practice in Brazil and, above all, not recommended by the World Health Organization, mainly because it does not lessen the importance of the dog as a reservoir, and utilizes drugs used in human treatment of visceral leishmaniasis (VL) [109]. Nevertheless, European countries legally established treatment since the twentieth century [110].
\nFrequent usage of these drugs in veterinary clinics may select resistant parasites due to variation in sensitivity of leishmania species, in addition to providing low parasiticide effect, thus interfering negatively in human treatment [111]. The lack of success for parasitological cure occurs mainly because it is an intracellular parasite and is located in less vascularized tissues where it can be difficult to obtain therapeutic doses, such as the vitreous body [112].
\nMany studies have been conducted in order to find an effective treatment for CVL, but drugs currently available are still inefficient, only allowing temporary remission of clinical signs. Besides, some have a high cost and produce toxic effects. Pentavalent antimonies (glucamine antimoniate—Glucantime® or sodium stibogluconate—Pentostam®) are widely used in CVL therapy protocols because they usually produce faster clinical remission but are often combined with allopurinol, since they do not prevent relapses [34]. A variety of drugs, such as amphotericin B, pentamidine isethionate, ketoconazole, fluconazole, miconazole, itraconazole, has been used either isolated or in combination and produced different results [111].
\nDue to the possibility of parasitic resistance to first-choice drugs, chemotherapeutic treatment options are limited. In addition, due to the high cost and long-term use, chemotherapy becomes an undesirable option for owners.
\nIn veterinary medicine, the first choice as chemotherapy for treatment of CVL is allopurinol, a leishmaniostatic drug that acts by inhibiting leishmania growth through DNA modification. It has low cost, but parasite resistance to it remains unknown. Allopurinol is however the only drug recommended by the World Health Organization, especially since it is little used for treatment of human leishmaniasis [113].
\nAntimonials are leishmanicidal drugs that hinder promastigote metabolism by inhibiting glycolytic activity. These are drugs of choice for human treatment of VL but are chemically similar to those that have been used in therapeutic protocols in dogs. Their toxicity and efficacy are related to the antimony content [113].
\nWhen assessing the therapeutic efficacy of Glucantime alone or associated with an antigenic extract of
In accordance with Ikeda-Garcia et al. [116], Manna et al. [118] monitored leishmania DNA load in infected dogs through real-time PCR, using a similar treatment protocol. Therapy resulted in clinical improvement accompanied by reduction in parasite burden, but even after a long period of treatment with allopurinol alone, parasites remained in tissues [116, 118].
\nMiltefosine is another drug used in human treatment that has been evaluated for canine treatment in recent years. It is a phospholipid antibiotic of broad spectrum with leishmanicide effect that improves the activation of both macrophages and T cells [119]. After evaluating efficacy of three treatment protocols for dogs naturally infected with
Some studies seek to associate chemotherapeutic treatment to immunomodulatory drugs, which plays a role in therapeutic protocols by controlling clinical signs and in prevention protocols by enhancing the immune cell-mediated response through activation of macrophages via helper T cells, in order to destroy phagocytized microorganisms. Domperidone is a receptor antagonist of dopamine D2 that has been used as well. When orally given to naturally infected dogs, results showed a reduction of clinical signs and titers of anti-leishmania antibodies [121]. In Spain, Sabaté et al. [122] used a treatment protocol with domperidone in seronegative dogs in an area with high prevalence of
Amphotericin B is a broad-spectrum macrolide antibiotic produced by actinomycete
Athanasiou et al. [124] investigated the effectiveness of aminosidine sulfate, a leishmanicide antibiotic of the aminoglycoside class, in the treatment of dogs naturally infected. They observed reduction in clinical signs and parasite density, in antibody titers through indirect immunofluorescence, and in prevalence of positive dogs using PCR 3 months after the end of the experiment. These findings can be explained by direct action of the drug as well as activation of cellular immunity. However, more studies are required to prove its therapeutic efficacy for CVL, especially considering its affordable price to owners and market availability [124].
\nDespite the research on efficacy of different classes of medications for CVL treatment, no great progress has been done regarding toxicity or parasitological cure, highlighting the necessity for evaluation of new formulations and medicaments to be used exclusively for treatment of CVL.
\nImmunotherapy can be an effective addition to chemotherapy, as it induces effector immune response faster than the isolated use of chemotherapeutic drugs [125]. In a trial, the combination of N-methyl meglumine antimoniate (Glucantime®) and lyophilized recombinant vaccine Leish-110f®, together with adjuvant monophosphoryl lipid A plus (MPL-SE®) to treat symptomatic animals naturally infected with
Borja-Cabréra et al. [127] evaluated the efficacy of immunotherapeutic vaccine Leishmune® administered alone, both in commercial formulation enriched with saponin and in laboratory formulation, compared to its use in combination with amphotericin B and allopurinol, in dogs naturally infected with
Joshi et al. [128] used Balb/c mice in order to verify in vivo therapeutic potential of the first generation of vaccines with dead
Immunotherapy is often considered for CVL prevention and control as a preferable alternative to euthanasia, due to the absence of a low-toxicity chemotherapy treatment and increasing resistance. According to Grandoni [129], vaccines are regarded as the best tool for eradication of the disease, particularly because it reduces the incidence of new cases, considering that the immune system fails to efficiently control the infection as it mediates a weak protective cell response. This relates to a dichotomy between the trigger of a Th1 response related to resistance and a Th2 response associated with susceptibility to infection, increased parasitic load, and strong but ineffective humoral immune response [129].
\nAccording to Joshi et al., an effective vaccine must induce a strong and long-lasting Th1 response as to prevent the initial establishment of infection: by definition, a prophylactic vaccine [128]. However, when it comes to a disease caused by an obligate intracellular protozoan, the aim is to at least control progression to severe disease and prevent transmission from host to vector, hindering maintenance of the epidemiological cycle.
\nSo far, vaccines formulated for CVL include dead parasites, protein components or parasite subunits, purified cell fractions, vector salivary recombinant proteins, and viral particles that encode parasite’s virulence factors and plasmid DNA [130]. Leishmune® (Zoetis Animal Health) was the first vaccine approved for commercial use in Brazil, in 2003. However, in 2014 the Ministry of Agriculture, Livestock, and Supply (MALS) halted manufacturing and marketing licenses due to problems in phase III. It consists of a glycoprotein antigen that binds recombinant fucose mannose which was able to stimulate good cellular immune response, decreasing IL-4, and activate CD4+ T cells, producing TNF-α and IFN-γ, important cytokines in resistance [131, 132]. Accordingly, a study done by Borja-Cabrera et al. found that the vaccine induced a long-lasting protective effect of humoral and cellular immunity, along with disappearance of clinical signs and parasitemia [133].
\nLeish-Tec® (Hertape), a vaccine comprising recombinant protein A2 as antigen in adjuvant saponin QuilA, continues to be marketed in Brazil since 2008, when it was recorded by the MALS. It has been demonstrated to offer partial protection against
Despite increasing progress in production of vaccines against CVL in Brazil and worldwide, there is much to be improved regarding the induction of durable and efficient cellular and humoral immune response. Moreover, new affordable vaccines ought to be produced for the population, since those available in the market so far are expensive and not viable for use in public health.
\nThe clinical diagnosis of CVL is challenging, as signs are usually not specific for the disease; laboratory assays are therefore of paramount importance. Moreover, as the dog is considered to be the major reservoir in Brazil, serological assays constitute the basis to identify infected dogs and to direct public health actions aiming the disease control.
\nThe indirect immunofluorescence antibody test (IFAT) was established as the standard serodiagnosis in public health programs more than 40 years ago. It was later substituted by an ELISA based on crude leishmania antigens [111] and more recently by a recombinant ELISA and an immunochromatographic rapid test for detecting K26/K39-reactive antibodies in canine sera [136, 137]. According to the recommendation from the Brazilian Ministry of Health, sera collected from dogs in seroepidemiologic surveys as part of the Leishmaniasis Control Program are first screened using the fast immunochromatographic assay (known as dual-path platform (DPP)), and the positive samples are retested in the recombinant ELISA. The approach undoubtedly speeds up the screening [138], but due to the DPP low sensitivity in cases of sera from asymptomatic dogs [137, 139, 140], a sizable set of infected dogs possibly remains in the endemic areas, jeopardizing the effectiveness of control actions.
\nPrivate laboratories used to rely in a single result obtained by the use of a commercial recombinant ELISA kit (ELISA S7) registered at the Brazilian Ministry of Agriculture, Livestock, and Supply for the diagnosis of CVL (www.biogene.ind.br). More recently, some fast immunochromatographic assays started to be used, such as the Alere assay [141], but high costs preclude their adoption in the routine diagnosis. A recombinant K39-based ELISA developed for research use only (http://www.inbios.com/kalazar-detect-elisa-system-for-visceral-leishmaniasis-intl/) has also seen some use in routine commercial CVL diagnosis.
\nThe official recombinant ELISA assay and the ELISA S7 have similar sensitivity and specificity indexes and perform equally well in the identification of seropositive, supposedly infected dogs. They also do not display significant rates of positive reactions in cases of vaccinated dogs. Other serological assays, e.g., the direct agglutination (DAT), are not easily available in Brazil and were never adopted in private or public labs. Although new antigens have been described in the last years (e.g., [142]), their commercial use in serodiagnosis is still uncertain. Although available as commercial kits (http://www.genesig.com/products/9332?gclid=CNXfgtXc_c4CFcoHkQodMm4Ctw), PCR assays are seldom used and have limited application for the routine diagnosis.
\nAs the existing recombinant ELISA assays have high sensitivity and specificity even in the serodiagnosis of CVL in asymptomatic dogs, one could argue against the need of new laboratory tests. However, claims of cross reactions with babesiosis and other common canine infectious diseases [138] continue to stir dissatisfaction.
\nIn conclusion, no diagnostic breakthroughs have been described and no innovative technology was introduced in the market in the last years, and there are no evidences that this scenario will be changed in the near future.
\nVisceral leishmaniasis control activities focus on reducing morbidity and mortality through early diagnosis and treatment of human cases, monitoring and euthanasia of seropositive dogs and sand fly population control via entomological surveillance such as chemical control. Additionally, they include education and health activities that involve joint actions aiming to improve population’s quality of life, such as provision of basic sanitation and proper trash disposal [143].
\nIn Brazil, the Visceral Leishmaniasis Control Program (VLCP) recommends surveillance, preventive and control measures of human and canine visceral leishmaniasis [11]. Epidemiological surveillance aims to reduce mortality and morbidity rates through early diagnosis and treatment of human cases and to reduce the risk of transmission by controlling reservoirs and vector populations. Surveillance comprises entomological surveillance of human and canine cases. What is set at national level for epidemiological surveillance of VL, emphasizing canine population, is described in the following paragraphs.
\nThrough epidemiological analysis of VL in the state or municipality, transmission areas are classified in areas with VL cases or silent areas (without cases). Areas with cases are those with record of a first confirmed case, those with sporadic, moderate, and intense transmission and those undergoing outbreaks. Silent areas or areas without cases are classified as vulnerable (receptive and unreceptive) or not vulnerable.
\nEntomological surveillance aims to gather quantitative and qualitative information about
In regard to dogs, surveillance focuses on suspect canine cases (symptomatic animals in endemic or outbreak areas) and on those confirmed by (a) laboratory criteria, symptomatic and positive in serological and/or parasitological test; (b) clinical and epidemiological criteria, symptomatic from endemic or outbreak areas without diagnostic confirmation; and (c) infected dogs, asymptomatic and positive in serological and/or parasitological test. When a canine case is identified, delimitation of the area to be investigated is among the surveillance actions to be taken. In those areas, active search for symptomatic dogs must be carried out for parasitological examination, and if the agent is found, serological survey of all animals in the area must be done in order to evaluate local prevalence and to implement appropriate measurements.
\nSample and census serosurveys must be performed as monitoring activity. The sample serological survey must be carried out in silent and receptive municipalities with
Preventive measures regarding canine population are (a) control of errant canine population, (b) donation of dogs after performing negative serological tests, (c) vaccination against CVL, (d) the use of fine mesh screen at individual or collective kennels, and (e) the use of collars impregnated with deltamethrin 4%.
\nCanine reservoir control measures consist in euthanasia of seropositive dogs and/or positive in parasitological tests, besides disposal of the bodies in accordance with the provisions of RDC Resolution No. 33, of February 25, 2003, from the National Agency for Health Surveillance.
\nIn Brazil, since 2000, as part of the decentralization process undergone by the National Health Foundation (FUNASA), the states’ federal district and municipalities became responsible for operating assistance, epidemiology, and disease control activities. They now receive almost all movable property, allocated in all federal units and more than 26,000 servers, and resources for maintenance of the transferred responsibilities [144]. However, despite the decentralization and recommendations by VLCP, the action taken toward canine reservoirs have been mainly restricted to areas of human case occurrences, that is, after a human case confirmation, canine serological survey follows in the surrounding area, and later, euthanasia of animals found seropositive in screening (DPP®) and confirmatory (EIE-Biomanguinhos) tests. Individual preventive measures such as vaccination, coverage of kennel doors and windows with mesh screen, and collars impregnated with deltamethrin 4% are restricted to animals whose owners have relatively high economic standard.
\nSeveral factors hinder the fulfillment of activities imposed by VLCP. Some of them are the lack of federal funding; insufficient staff to perform activities related to VL and other endemic diseases; prioritization for control of other endemic diseases such as dengue, Zika, and chikungunya; expansion of transmission areas; and interference of veterinarians, animal owners; and nongovernmental organizations (NGOs) regarding euthanasia of reservoirs, as such procedure generates controversy regarding its control efficacy, although recommended in Brazil [145].
\nFunding provided by The National Science Center (Poland) grant No. 2014/13/B/NZ4/03832.
As already mentioned in other chapters, milk whey is a liquid by-product generated after obtaining cottage cheese or curd (proteins coagulated by acid and heat), also known as cheese whey, that for many years has been considered a waste product, and sent to bodies of water, soil, and sewage systems. However, currently it is used due to its multiple nutritional and functional properties [1].
In Mexico, the production of whey in 2016 was estimated at 1,010,000 tons, 47% of which was discharged to soil, drains, and bodies of water. Despite the fact that multiple uses have been found to cheese whey, this has become a serious environmental problem [2]. This by-product is composed of water, lactose, proteins, peptides, fat, and mineral salts [3]. One of the peptides of interest is glycomacropeptide (GMP), which is obtained after the coagulation of milk κ-casein during cheese production and represents 15–20% (w/w) of the total proteins contained in milk whey [4].
GMP is the C-terminal fragment released by the proteolytic action of the endopeptidase chymosin (renin) on κ-casein during the initial stages of cheese making, or by the action of pepsin during the gastric digestion. κ-casein is hydrolyzed at phenylalanine105-methionine106 bond, forming two very different polypeptides. One is called para-κ-casein (residues 1–105), and it is slightly cationic at pH 6.6, hydrophobic and poorly soluble, which remains in cheese curd; and the other is GMP (residues 106–169), that is strongly polar so diffuses into the aqueous phase, being eliminated during the draining with the cheese whey (as reviewed in [5]).
GMP has 64 amino acid residues, with an isoelectric point (pI) between 4 and 5. Fifty percent of GMP is deglycosylated and is known as caseinomacropeptide (CMP) [5]. However, milk GMP can present different types of carbohydrates, such as: sialic acid, galactosyl, and N-acetylgalactosamine, which generate different glycosylated forms of the molecule. GMP is rich in amino acids such as proline, glutamine, serine, and threonine, but deficient in tryptophan, tyrosine, phenylalanine, and cysteine. The absence of aromatic amino acids in its primary structure causes that GMP does not present absorption at the wavelength of 280 nm. However, GMP can be detected at wavelengths between 205 and 226 nm and absorption differences between 210 and 280 nm are used for the characterization of GMP (as reviewed in [5]). The composition of GMP can be variable and depends on the source of serum and the fractionation technology used in its isolation [3] (Figure 1).
Primary structure of bovine GMP variant A and B, where ● indicates its three phosphorylation sites and ▲ the most important glycosylation sites. Modified from Thomä-Worringer et al. [
As reviewed by Neelima [7], the three-dimensional structure of GMP cannot be evaluated due to its crystallization which is not possible, so it can only be seen from a purely theoretical approach. GMP is a peptide that does not possess defined secondary and tertiary structure. However, three-dimensional structure of GMP has been predicted by means of protein modeling and shows that a large part of the peptide has a strong negative charge, whereas there are three small domains with a positive charge at the N-terminal end. At pH 7.0, its mean value of the hydropathy is −0.322, and GMP is more hydrophilic than hydrophobic. The hydropathy value decreases when glycosylation of GMP increases, due to the greater amount of sialic acid residues.
The use of GMP is growing, since it is a bioactive peptide with unique nutritional and nutraceutical properties. Many biological activities of GMP have been reported, highlighting antimicrobial, anticariogenic, gastric acid inhibitory, cholecystokinin (CCK) releasing, prebiotic, and immune modulatory. Of particular interest is GMP’s capacity to modulate the immune response, due to its potential use in treatment or prevention of different immunopathologies.
One of the first antimicrobial effects observed in GMP was due to its ability to bind cholera toxin and
There are several
In association with this antimicrobial effect, an anticariogenic activity to GMP has been demonstrated. Firstly,
Several studies have related GMP with the inhibition of gastric secretion. First ones were mostly developed using dogs by a group of Russian researchers. The first evidence that GMP inhibits gastric secretion was showed by Shlygin and co-workers [18] using gastrin to evoke it. Subsequent works demonstrated similar effect using different gastric secretion stimulants [19]. Some years later, it was proposed that this inhibitory effect was caused by a GMP fragment rather than the whole molecule [20, 21]. Later, injecting dogs with a protein fraction obtained from the gastric content of unweaned rats, it was observed an inhibition in dog gastric secretion to a food stimulus [22]. This inhibitory action was similar to that induced by GMP in dogs. GMP was also demonstrated to inhibit gastric motility after its intravenous injection in dogs [23]. All these experiments point out that at physiological conditions GMP may be playing a crucial role in the preservation of active milk proteins in newborn animal during natural breast feeding. In addition to dogs, other experimental models such as rats, pigs, and calves and also isolated organs were used to demonstrate that GMP induces gastric secretion inhibition in association with a decrease in blood of some regulatory digestive hormones, as gastrin and CCK (as reviewed in [24]). However, variations in used gastric stimuli, GMP dose, and origin, via of administration and experimental approach may be the cause of the differences in the reported intensity to this GMP activity.
Related with the effect of this bioactive peptide on digestive hormones, GMP has also been associated with appetite control. Several
For many years, the prebiotic properties of GMP have been discussed. The first evidence that GMP might possess prebiotic activity arose with the bifidobacterial growth promoting effect of human’s colostrums and milk by
In the last years, several research groups have demonstrated that oral treatment with GMP modifies
GMP has been shown to modulate the immune response in a number of different ways. First, we summarize literature reports about regulatory activity of GMP on immune cells demonstrated by
In relation to the immunomodulatory effects of GMP on immune cells, different
On the other hand, GMP is also able to downregulate dendritic cell response to LPS by inducing a slight but significant decrease in the production of IL-6, IL-1β, and TNF-α, but without changing the production of IL-12 and IL-10 [49]. Strikingly, the regulatory effect of GMP on neutrophils is the opposite, as it improves proliferation and phagocytic activity of the human macrophage like cells U937 [52]. However, the observation that both polypeptide and carbohydrate portions are essential for GMP biological effects is reinforced in this study, as peptides of pepsin-digested GMP and sialic acid-rich GMP fractions significantly enhanced cell proliferation and phagocytic activities stimulated by non-digested or asialo-GMP on U937 cell. Also, an upregulatory effect of GMP on production of IgA by LPS-stimulated splenocytes has been reported, being correlated with an increase in the population of IgA positive cells [53].
There are several studies that analyze the immunomodulatory activity of GMP on immune response when it is orally administered to experimental animals. In the context of splenocytes response to mitogens, two
The effect of orally administered GMP on humoral immunity has also been studied. Mice fed with GMP have shown suppressed levels of specific IgG to dietary and injected antigens, with no change in IgM, IgA, and IgE antibody response [54]. In this regard, a recent study showed that oral administration of GMP to mice resulted in a greater number of IgA positive plasma cells in the intestinal lamina propria [56]. All these results [54, 56] plus
Martínez-Augustin and co-workers [57, 58] have studied the immunomodulatory action of GMP in experimental models of intestinal inflammation. They have demonstrated that GMP administered orally to rats exerts an anti-inflammatory effect in ileitis and colitis induced with trinitrobenzenesulfonic acid (TNBS); said anti-inflammatory effect shows a degree of efficacy similar to that of sulfasalazine, a drug widely used in the treatment of inflammatory bowel disease. GMP was shown to protect rats from TNBS-induced colonic and ileal inflammatory damage, by reducing the damage score and the extent of necrosis, and also by diminishing the increased alkaline phosphatase colonic activity and inducible oxide nitric synthase expression. IL-1β and IL-1ra messenger RNA levels were significantly decreased in colon as a consequence of GMP administration; and myeloperoxidase activity and levels of IL-1β and IL-17 were decreased in ileum. Initially, the authors assumed that the action mechanism of GMP was not related to anti-oxidative activity or to regulatory cell induction, as glutathione or TGF-β levels in colon and Foxp-3 in ileum were not affected [57, 58]. However, when GMP was orally administered to rats, an increase on Foxp3 expression in spleen cells was observed, although secretion of cytokines by
In recent years, a Mexican laboratory led by Salinas [55, 59, 60, 61] has focused on the study of the immunomodulatory activity of GMP in experimental allergy models. They found that oral administration of GMP to rats before and during sensitization with allergen significantly reduces the level of allergen-specific IgE in serum, and also decreases the proliferative response and the production of IL-13 by splenocytes stimulated by the allergen [55]. Treatment of animals with GMP also protected them from systemic anaphylaxis as GMP administration increased survival rates and lessened signs of severity of anaphylactic shock. Moreover, GMP reduced the intensity of urticarial inflammatory reaction when sensitized animals were intradermically challenged with the allergen [55]. With these results, it was demonstrated the immunomodulatory properties of GMP on allergic sensitization and its beneficial effect on clinical signs associated to early-phase allergic reaction. Then, they investigated whether GMP may impact on late-phase and chronic inflammatory allergic reactions, using two experimental models that after repetitive exposure to allergens displayed local recruitment and activation of immune cells with persistent production of inflammatory mediators in affected tissues, together with substantial changes in the extracellular matrix and alterations in structural cells [62]. Specifically, they used experimental models of asthma and atopic dermatitis prophylactically administered with GMP, that is to say, prior to and during pathology establishment. As expected, GMP intake resulted in reduction of IgE titers in serum. In addition to this, in asthma model, GMP substantially decreased blood eosinophilia and suppressed the recruitment of inflammatory cells to the bronchoalveolar compartment. GMP also inhibited eosinophils infiltration, goblet cells hyperplasia, and collagen deposit in lung tissue [59]. Equivalent results were obtained in allergen-induced atopic dermatitis model, where GMP reduced the intensity of cutaneous inflammatory process and edema, abolished pruritus, and reduced eosinophils recruitment and mast cells hyperplasia in dermis [60]. In both models, expression of IL-5 and IL-13 was markedly inhibited in lung and skin, while expression of IL-10 was increased. Their research then turned to the mechanism by which GMP modulates the allergic response. They demonstrated that GMP administration increases the amount of
Finally, there are few studies that analyze the role of GMP on cancer. In a rat model of pharmacological-induced colorectal cancer, oral administration of 100 mg/kg of GMP decreased the number of aberrant crypt foci although no effect was observed at doses of 10 and 50 mg/kg. On the other hand, there was no change in methylation and expression level of p16 and MUC2, two tumor suppressor genes [63]. Additionally, through an
Although more studies are needed in relation to some biological activities, current results propose GMP as a good candidate to be used as a functional ingredient in food industry.
Today, one of the objectives of the food industry is the development of novel food products with beneficial properties for health. For its different health benefits, GMP can be used in therapeutic and dietary foods, or as a functional ingredient in various special products, like oral care products.
It is crucial to demonstrate that GMP is hypoallergenic to be used in food compositions. In this regard, Takahashi and collaborators patented a food composition that contained GMP and a mixture of free amino acids (leucine, lysine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, arginine, histidine, and glycine) [65]. The composition presented good taste, good absorption and digestion properties, and a high nutritional value. They demonstrated that this composition was hypoallergenic, as after repeated injections of the GMP composition together with an adjuvant used to induce experimental allergy in mice, no antibody against GMP was detected in serum by Ouchterlony. Although this method is not very accurate, GMP hypoallergenicity was later corroborated by Milkkelsen and collaborators using ELISA test to show absence of specific antibodies in mice after being sensitized both systemically or orally with GMP [66].
Due to the particular amino acid composition of GMP, devoid of aromatics amino acids (phenylalanine, tryptophan, and tyrosine), it can be used for special diets of people suffering from phenylketonuria (PKU), being an adequate choice as a source of proteins [67]. On the other hand, GMP has low amount of methionine but high amount of branched chain amino acids (valine and isoleucine), which makes this peptide an excellent candidate to be used for the control of liver diseases, as this type of amino acids are good as caloric sources [68]. There is a patent to use of GMP to improve female’s health [69]. The inventors claim that administration of a composition comprising GMP can improve the health of the females. They used murine models fed with GMP composition and showed that females decreased final fat mass and percent body fat, when comparing with females that received a diet based on caseins or free amino acids as source of proteins. In relation to bone characteristics, femur length was larger in GMP administered mice, although only females showed less femoral weakness and greater bone mineral content and density as compared to those fed with amino acids or casein diets, respectively.
As previously mentioned, research results suggest that GMP has an effect on the feeling of fullness but this does not translate into a lower food intake [27, 28]. For an application in food intake regulation and in potentially body weight management, more work is required. Understanding dose, timing, and delivery mode, including food form and composition, in relation to the pattern of release of CCK, is needed for the use of GMP as appetite suppressant [70].
GMP has physicochemical properties that make it attractive for use as an additive in food products. According to studies on the functional properties of GMP, it can act as an emulsifier, foaming, and gelling agent.
GMP as an emulsifier presents stability to pH variations, which is attractive for foods that undergo pH changes during their process, such as the case of fermented milk products [71]. The best emulsifying capacity was obtained at alkaline pH. However, it has been observed that emulsions with GMP as emulsifying agent are not stable during storage when they have received thermal treatment [72]. Besides, GMP modified covalently with disaccharides or fatty acids can present an improved function and even increase its biological activity [73, 74]. Therefore, in order to modify the emulsification activity of GMP, this peptide has been conjugated with other molecules such as lactose [73] and fatty acids [74]. The conjugation of GMP with lactose was carried out through the reaction of Maillard, and this conjugate showed a better emulsifying capacity without significantly reducing the solubility of GMP [73].
Currently, foams have many industrial uses of great importance in the production of beer, soaps, whipped cream, shaving cream, aerosols, etc. The formation of a foam requires the participation of a surfactant capable of diffusing to the air/water interface to lower the surface tension. GMP complies with this property, although the foams formed with GMP are stronger or more stable when combined with other foaming proteins [75, 76]. In order to improve the foam properties of the proteins, synergistic mixtures of biopolymers and pH variations have been made that can modify their charge and, consequently, their foam ability. In relation to this, by combining sodium caseinate with GMP, synergistic interactions take place between these molecules on foaming and on stability at pH 5.5 [77]. Non-glycosylated GMP has better foaming properties than glycosylated GMP [78]. This is due to the glycosidic structures favor a combination of hydrophilic and electrostatic effects, which prevents an orderly adsorption of the glycosylated GMP molecules at the air/water interface; whereas, non-glycosylated GMP forms a very stable network at the interface.
On the other hand, gels are semi-solid systems that consist of a network of solids (three-dimensional network of polymers) with an inside trapped-liquid. They are of great importance in food and pharmaceutical industry as many gelled products are manufactured throughout the world (gummies, gelatins, jelly jams, bakery fillings, and therapeutic or cleaning agents). Generally, gelling agents are proteins and polysaccharides. Gelling properties of GMP has been studied and it is known that its gelation depends on pH and temperature, reporting that even aqueous solutions with low GMP amounts can be gelled at pH below 4 [79]. Besides, GMP can potentiate gellying capacity of other substances. Thus, by fermenting goat milk to which GMP was added, a more ordered and structured gel was obtained, in addition to obtaining a better elasticity in it, as compared to that obtained when whey protein concentrate was added [80]. The influence of GMP on the gelation made by gelatin has also been studied and when these two compounds are mixed, lower concentration of both substances are need to get a gel as compared with the ones need when they are used separately [81]. This synergistic effect in gelation is very important in the food industry for the preparation of desserts and foods based on gels.
Dental caries is one of the chronic diseases that most often affect humans. Due to the anticariogenic and remineralization properties demonstrated to GMP and previously reviewed in biological activities section, nowadays GMP is being incorporated to some oral care products [15, 16, 17].
One of the problems presented by the dairy industry is the adulteration of milk with whey cheese, which is very cheap and not detected by sensorial tests. Cheese whey does not cause harm to health, however, it affects milk-derived products manufacturers financially and can affect the consumers nutritionally, so the addition of cheese whey is considered a fraud. Due to GMP present in cheese whey, the detection of this peptide may indicate the addition of cheese whey to milk. Some of the methods that detect GMP as an indicator of the presence of cheese whey are described below.
High performance liquid chromatography (HPLC) has been widely used to identify GMP as indicative of milk adulteration with cheese whey. In order to carry out the analysis, it is necessary to pre-treat the samples with TCA to precipitate proteins that can interfere (k-casein) and to concentrate GMP [86]. Similarly, a rapid and sensitive HPLC method on a gel permeation column was developed to detect GMP to follow the hydrolysis of k-casein by chymosin in milk [87]. The only pretreatment given to samples was addition of TCA (final concentration 8%) to precipitate the interfering caseins and whey proteins. This method was widely used by several researchers to analyze different samples, such as skimmed milk powder [88]. Cation-exchange chromatography has also been used to detect GMP, previously removing caseins from whey samples by precipitation with HCl at pH 4.6, neutralizing with TCA at 2–8% and analyzing supernatants [89]. On the other hand, a Reversed-Phase HPLC (RP-HPLC) method was developed and validated to separate and quantify GMP and was demonstrated to be precise, sensitive, and reliable [90]. The determinations were performed in the linear range of 15–200 μg/mL and the detection limit was 2 μg/mL. The method was applied to the analysis of rennet and acid whey, whey protein concentrates produced by the dairy industry, and also for the detection of rennet whey in powdered milks.
The European Commission uses two methods to detect the presence of cheese whey in milk: a gel permeation chromatography and subsequently a RP-HPLC as a confirmatory test [91]. However, it has been shown that the sensitivity of this method is affected by the presence of acidified rennet whey, which makes it difficult to detect the addition of whey [92]. Besides, the HPLC methodology used to analyze compounds like GMP in dairy products usually includes extractions with solvents, sample’s preparation require a lot of time and reactives, the equipment is very sophisticated and demands trained personal.
Spectroscopy has also been used to detect GMP. The medium infrared spectroscopy (MIR) was used to analyze milk powder in order to detect GMP as adulteration parameter. Although this method is fast, it is not widely used because derived spectra are not very easy to interpret, in addition to its high cost [93]. On the other hand, by liquid chromatography/electrospray coupled to mass spectrometry, milk products were analyzed and it was able to quantify GMP from concentration of 10 pmol, although the method was not used to detect milk adulteration [94].
Immunoassays are analytical methods of great application in the food area, and have the advantages that they are quick, sensitive, and that the sample to be analyzed requires little or no treatment. Several immunochemical methods have been developed in order to identify and quantify GMP in milk. Firstly, it is necessary to produce antibodies against GMP and later, these antibodies can be used for the development of the different immunochemical methods that detect it. Some of these assays are described below:
In summary, different techniques and methods have been developed and used to detect GMP as an index of adulteration of milk with cheese whey. Some of them can also be used to quantify GMP in food products. The aim of this area of research is to achieve one that bring together being cheap, fast, easy to develop, and to interpret the results, with high sensitivity and a limited sample processing. These characteristics will allow people to use them at the time and place of milk reception.
GMP possesses several nutritional and health promoting properties. Among them, it exerts important modulatory effects on the immune system that are beneficial in a number of different inflammatory conditions. GMP immune response mechanism of action might be mediated by increasing healthy intestinal microbiota, by inhibiting splenocyte proliferation, by promoting both local and systemic regulatory environment, and also by directly modulating immune cell functions. More research is needed to support these findings, as we cannot exclude a possible effect of products derived from GMP digestion on
We appreciate the support given to the Autonomous University of Aguascalientes for the publication of this chapter.
Authors declare that there is no conflict of interest between the authors of the chapter entitled: “Glycomacropeptide: Biological activities and uses.”
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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