Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n
"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"1915",leadTitle:null,fullTitle:"Practical Applications of Agent-Based Technology",title:"Practical Applications of Agent-Based Technology",subtitle:null,reviewType:"peer-reviewed",abstract:"Agent-based technology provides a new computing paradigm, where intelligent agents can be used to perform tasks such as sensing, planning, scheduling, reasoning and decision-making. 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1. Introduction
Biofilm formation is structured accumulation of fastidious microorganisms attached on inanimate objects or compact surfaces that extensively have been examined in the past decades because they particularly cause infections and more often responsible for chronic infections [1, 2, 3]. They are predominantly problematic due to their antimicrobial resistant properties and their ability to evade host defense mechanisms, which substantially hinders disease treatment in the hospital [1, 2, 3, 4]. Bacterial biofilms are ubiquitous in nature and harbor phenotypic adaptations in the environment with respect to broader perspective [1]. The nature of single cell organisms enables them to adhere to each other and form a “complex structure,” which assists to survive under adverse environmental condition. The biofilm formation occurs from planktonic bacteria due to environmental changes and involves in conjugation gene transfer “multiple regulatory network” from one bacterium to another in response to environmental stress [5, 6, 7, 8, 9]. This type of cell-to-cell adhesion and gene transformation changes the expression of surface molecules, virulence factors, and nutrient utilization that enables their survival under unfavorable environmental condition [8, 10, 11, 12, 13, 14, 15, 16, 17].
Bacteria are cocooned within the biofilm and form extracellular matrix, which represents 90% of the biomass [18]. The matrix as a stabilizing scaffold for the three-dimensional structure is composed of extracellular polymeric substance (EPS) along with extracellular DNS and carbohydrate binding protein [19, 20, 21]. Nutrients are trapped by the resident bacteria in the matrix and water is retained efficiently via H-bond interaction with hydrophilic polysaccharides [18, 22]. The composition of extracellular polymeric substance (EPS) is modified in response to alterations in nutrient availability [23, 24] by certain enzyme secretion of bacteria, thus tailoring biofilm formation to the more specific environment [23, 25]. Therefore, the skeletal components of the extracellular matrix are highly hydrated and provide high tensile strength that enables bacteria to exchange their DNA by conjugation and promote cell-to-cell interaction while defending the biomass from predation, radiation, desiccation, oxidizing molecules, and other dangerous agents [18, 26, 27, 28].
The multifaceted nature of biofilms that allow the bacteria to form a community, i.e., division of labor and express their virulence factors in response to local oxygen and nutrient availability, makes them resistant against different antimicrobial agents [29, 30]. Some studies have shown that there are presence of nondividing metabolically inactive recalcitrant bacteria within the biomass [29, 31], which play very crucial role to cause tolerance against broad-spectrum antimicrobial drugs. The matrix protein inside the host cell protects bacterial biofilm against innate immune defenses, i.e., phagocytosis and opsonization [32]. The spread of other virulence factors inside the host cell and drug resistance marker is due to the cell-to-cell interaction [15]. Thus, biofilm-forming pathogens retained and adhere to the infected surface and cause recalcitrant and chronic infection, i.e., upper respiratory tract infection (particularly, Pseudomonas aeruginosa) [33, 34], dental decay (mixed culture of Streptococcus mutans, and other pathogens) [35], ventilated-induced and other device-associated infections (Escherichia coli, Klebsiella spp., Enterococcus faecalis, Staphylococcus aureus, etc.) [36, 37], urinary tract infections [Proteus spp., uropathogenic E. coli (UPEC)] [38]. In particular, immunocompromised patients are the most common target to all these biofilm-forming pathogens, causing a devastating impact on patients, and in many cases, leading to death. Here, we analyze the formation of intracellular and extracellular biofilm which is the underlying factor for various medically important microorganisms. Given the recalcitrance and prevalence of infections caused by biofilm-forming pathogens, we discuss knowledge about the most current progresses in the advancement of novel strategies of biofilm.
2. Extracellular formation of biofilm
2.1 Bacterial attachment on surfaces and what does make it adhere to object surface?
Bacterial biofilm growth, subsequent maturation, and aggregation consist of irreversible and reversible stages, which involve various conserved and species-specific aspects. At the first stage, the bacteria are introduced on the surface; a process of at least a part of stochastic that is driven by gravitational forces and Brownian motion, and usually influenced by nearby hydrodynamic forces [39, 40]. Microorganisms encounter with repelling or attractive forces—within the niche that alter depending on ionic strength, pH, nutrient levels, and temperature. Bacterial cell wall composition, along with medium properties, affects direction and velocity toward or away by the contact surface of pathogens [39]. Motile bacteria utilize flagella in order to overcome repulsive and hydrodynamic forces, by having a competitive advantage. The main function of flagella is to provide motility and initial cell attachment to the surface for various pathogens, including Listeria monocytogenes, E. coli, Vibrio cholerae, and P. aeruginosa [41, 42, 43, 44, 45]. In some species of bacteria, chemotaxis plays very important role in direct attachment to nutrient composition, for instance, mutations arise in CheR1 methyltransferase, which have been observed to vary the response of amino acid of P. aeruginosa and impair maturation of bacterial biofilm and attachment [46]. Some earlier studies have been shown that chemotaxis in E. coli is dispensable [5]; moreover, current observations revealed that the disruption occurs in the chemotaxis methyl accepting protein II and informs biofilm defects particularly in uropathogenic E. coli cells [47]. With respect to intercepting surface, bacterial attachment is facilitated by additional secreted molecules such as adhesin protein and extracellular adhesive appendages.
Initially, the attachment is reversible and dynamic during which pathogens can separate and rejoin planktonic biomass if agitated through repulsive forces [48], hydrodynamic forces—detach bacteria off from the surface. Some bacteria attained irreversible attachment in order to maintain a firm grip on the cell surface. Serotypes of other E. coli and uropathogenic E. coli depend intensely on the type 1 pili [5, 40, 49, 50, 51]. Uropathogenic E. coli harbors several pili systems (means CUP system), which mediate adhering to a specific niche [38]. Attachment on the bacterial surface is facilitated by the adhesion protein (FimH), which identifies mannosylated moieties [50, 51, 52]. The adhesive protein (FimH) plays a critical role in the pathogenesis of uropathogenic E. coli because it facilitates adherence and causes invasion to epithelial cells of bladder in human, adheres to the human uroplakin and is also critical in preclinical murine cystitis model, which causes human disease [51, 53, 54]. FimH is much more consistent to play a critical role in the virulence of human disease under positive selection [52, 53, 54, 55, 56].
Furthermore, antigen 43, curli fibers, and type 1 pili have been observed to facilitate attachment and cell-to-cell interaction on inanimate surfaces [57]. Curli fiber also mediates attachment to the extracellular matrix components in eukaryotes such as plasminogen, fibronectin, and laminin [58]. Pseudomonas aeruginosa, for instance, uses various additional organelles, which assist in adherence to the surface, irreversibly. Contrary to UPEC and P. aeruginosa, Gram-positive bacteria (Enterococci) are lactose producing, nonmotile, and recently identified to contain nonadhesive (pili) that mediate attachment to the extracellular matrix components in eukaryotes. Examples of these include Ace (E. faecalis) and SagA (E. faecium), which attach to the collagen protein [59] and surface protein (Esp). This has been observed to stimulate abiotic formation of biofilm on the contact surface specifically in E. faecalis [60]. Current studies showed the existent of biofilm-associated pili (Ebp) and also confirmed their contribution toward urinary tract infections, endocarditis, and biofilm formation and attachment [61].
2.2 Maturation of biofilm
Cell-to-cell interaction triggers specific intrinsic responses that cause changes in the gene expression, upregulating factors favorable to sessility especially for those involved in extracellular matrix protein formation [40]. However, relatively very little information is obtained about the matrix constituents with respect to E. coli pathogen. Initially, cellulose was recognized as essential components in E. coli pellicle biofilms and later on expressed with curli fibers in gastrointestinal E. coli strains [62]. Curli fiber plays a critical role in pellicles, for instance, curli fiber (amyloid) that leads to the pellicle biofilm formation. It also acts as a curlicide to prevent pellicle formation, and some of them have deficient to form pellicles (known as curli mutants) [63]. Further studies revealed that colonic acid and polyglucosamine (PGA) take part in biofilm architecture [64], while the PGA being predominant among the clinical strains, particularly in UPEC isolates. Thus, more detailed investigations are required for further characterization of extracellular matrix protein in E. coli. The composition of extracellular matrix protein has been extensively analyzed in P. aeruginosa and varies depending on external environmental conditions [65]. The primary components of EPS are Psl and Pel [25]. Psl enhances the attachment of P. aeruginosa to epithelial cells [66] and mucin, while the expression of Pel increased in small colony variants (SCV) isolated from the cystic fibrosis patients associated with Pseudomonas persistence in the airways of lung [67]. Moreover, intercellular interactions and biofilm stabilizations in P. aeruginosa are critical in response to environmental DNA (eDNA) [68].
Mature P. aeruginosa biofilm formations are more resistant to treatment with DNase as compared to young biofilms, demonstrating that eDNA remains stable because the components of EPS are not abundant during the initial stage of biofilm when the bacterial cells come to attach each other. In contrast, the concentration of eDNA increases during biofilm maturation stage due to the occurrence of bacterial cell lysis in response to quorum sensing mechanism of Pseudomonas quinolone signal (Pqs) [69]. In Pseudomonas, type IV pili play an essential role in the migrating pathogens to form aggregation in the area of high eDNA binding attraction [70]. The amount of eDNA to form biofilm structure has already been observed in E. faecalis. Some reports identified that biofilm formation in this organism is influenced by the affected autolysis of cells and intracellular release of DNA [71, 72]. Initial study reported that the mutant reduced the biofilm formation by 30% due to the lack of autolysin gene, Atn [59]. In another study investigated, it showed that specific stage of bacterial biofilm formation required temporal regulation by Atn for the release of DNA [73].
2.3 Matrix escape mechanisms
Bacterial mature biofilm provides a suitable living environment to the resident microorganisms for making compact surface adherence community, so as to share products and actively exchange their genetic materials by conjugation. Moreover, as biofilms mature, dispersal becomes a choice. In addition to passive dispersal caused by shear stress, the pathogen develops different ways to recognize environmental changes, which make it to stay within the biofilm. Bacterial biofilm dispersal occurs as a result of various clues such as oxygen fluctuations, modifications in nutrient availability, and increases in toxic products [74]. Biofilm dispersal is induced by the increase of extracellular iron in uropathogenic E. coli [75], while in Pseudomonas spp., it is due to the increased quantities of various nitrogen and carbon source [76]. The amounts of small molecules such as alterations in environment and changes in gene expression are monitored by various sensory systems [77]. Among various other signals, for instance, universal cyclic-di-GMP has been used in P. aeruginosa and E. coli causing implication in a shift between motility and sessility. Typically, an increase in the level of cyclic-di-GMP is favorable to sessility, while a reduction in cyclic-di-GMP induces upregulation of motility [78].
Recently, some results reported the factors responsible for such changes such as downregulation of extracellular polymeric substance, reduction of cyclic-di-GMP in bacterial biofilm communities, and upregulation of swarming and swimming motility [25]. Certain type of enzymes (such as alginate lyase) also participates in pathogen detachment from surface especially in P. aeruginosa [79], whereas in E. coli, the enzyme (CsrA) is responsible to repress the synthesis of PGA [80]. Along with that downregulation of EPS, certain molecules of surfactant are produced causing a reduction in cell-to-cell interaction. Moreover, studies identified that flagellated populations within the biofilms of P. aeruginosa migrate to other void surface in order to make colonies [65]. Initially, these colonies loosely attach to compact surface, but after maturation process, they make a hard shell in the surrounding and use the infected surface as a source of nutrient. Sometimes, live cells use dead cells as a source of carbon. When bacteria become dead, then live cells accumulate on it, bind to each other by sharing their genetic materials and form a compact layer that is usually very hard to break. Dead cells are also responsible for creating cavity within the bacterial biomass. The bacteria within the biofilm can be scattered by applying dispersal mechanism.
Due to dispersing nature of bacteria, they may have the ability to restart the biofilm formation process after encountering a favorable environmental condition [81]. This is another sophisticated mechanism of dispersal revealed by using B. subtilis, which could be prevalent among the bacterial species. Researchers reported that the pathogen (B. subtilis) lost its cellular integrity within 5–8 days and also found that disassembly of biofilm is associated with a mixture of different amino acids (D-tyrosine, D-methionine, etc.) that are formed during bacterial stationary growth phase [82]. These D-types of amino acids interfere with bacterial attachment to cell surface and perturbation to fiber dissociation, without influencing matrix component expression or bacterial growth [83]. In B. subtilis, the performance of biofilm is disrupted by the addition of D-type amino acid mixture [83]. Further studies showed that another factor such as norspermidine, which is produced by B. subtilis, works together with D-type amino acid leading to biofilm disassembly [84]. So, this type of association—norspermidine/D-type amino acid—is essential for the eradication of bacterial biofilm and makes them vulnerable to antimicrobial agents used in the hospital.
3. Bacterial intracellular biofilms
Gathering evidence have showed that numerous bacterial pathogenic species formerly considered as extracellular can retain within the host cell by adapting intracellular bacterial lifestyle that includes the bacterial communities having biofilm-like properties. First, a murine model of infection was used to assess the bacterial communities for UPEC [85]. Type 1 pili in uropathogenic E. coli bind to the receptor on superficial bladder cells [86], triggering to induce bacterial internalization. Toll-like receptor-4 (TLR-4)-dependent process used to expel out from inside the UPEC [87], but certain bacteria elude exocytic procedure and leave out from the cytoplasm of host cell, where they duplicate into intracellular bacterial communities (IBCs) [85]. Several developmental stages lead to the process of IBCs that indicate distinct morphological features [85]. After passing first 6 h ensuing bladder inoculation, UPEC rapidly divides (replication time 30–35 min) causing small clusters associated with loosely attached rods (during early IBCs), having a coccoid shape and an average bacterial length of about 0.7 mm. The bacterial exponential growth rate dramatically drops between 6 and 8 h, exceeding replication time to 60 min. This is the second stage where bacteria accumulate and are tightly packed within the biofilm and organized a compact sphere-shaped structure (mature-stage IBCs) (Figure 1).
Figure 1.
Schematic diagram of the development of IBC cascade in uropathogenic E. coli (UPEC), taken by scanning electron microscope (SEM) images indicating different structural changes from attachment to dispersion and fluxing.
The amount of IBCs is found between 3 and 700 in an infected patient’s bladder—IBCs are composed of 104–105 bacterial cells [88]. There are numerous fibers surrounded on IBC bacteria that originate from the surface of pathogen and enclose pathogens in individualized sections. One of the main components present on the surface of IBCs called polysaccharide (sialic acid) that provides protection from the attack of immune system and environmental stress. The heterogeneous nature of IBCs, such as extracellular bacterial biofilm, composed of different subpopulation having distinct gene expression systems [89]. As IBCs expand, they induce the bacterial biofilm to cause interruption against cell membrane of host, producing a pod-like structure on the infected cell surface. Ultimately, UPEC detaches as filament or single rod at the IBC boundary and the infected cells are flux out into the lumen of bladder where can invade epithelial cells and restart the process through binding [85]. The inhibitor (SuIA) of cell division has been observed to be crucial for dispersal and filamentation of UPEC from the bacterial biofilm. The patients suffered from urinary tract infections (UTIs) are more likely observed with the UPEC filaments in their urine, but not in comparison with healthy controls [90].
The formation of IBC is prevented by intense molecular blockages and during acute infection—development of chronic cystitis—the IBC numbers are higher, representing the significance of intracellular pathways in the pathogenesis of UTIs [88]. The cycle of IBC is dependent on FimH, causing interruption in the expression of type-1 pili after invasion to host cell, and disrupts normal development of IBC due to attenuation of UPEC [54]. The two-component system (QseBC) is a key factor influencing curli expression, formation of IBC and type-1 pili. Some studies indicated that the intracellular pathway of UPEC is necessary for the TCA cycle completion [47]. The techniques such as qPCR and DNA microarray analyses interpreting the UPEC expression patterns within IBC pathogen exposed that acquisition of iron in bacteria is upregulated, representing the significance of system biomass formation [91]. While in clinical isolates of UPEC, the iron acquisition patterns are prevalent [92]. Moreover, the pathogen Klebsiella pneumoniae is more commonly seen in community- and hospital-acquired infection. About up to 5% forms intracellular communities and is more predominant in hospitalized diabetic patients [93]. Likewise to UPEC, the Klebsiella pneumoniae invasion is mediated by type-1 pili and formation of IBC, although the differences occur in the expression kinetic of pili and filaments [90]. The ability to occupy an intracellular niche and persist within the host cell through transitioning from single microbial cell to the multicellular community is not confined to uropathogens. Researchers showed that by using different animal models and cell line of acute lung infection, the cluster formation occurs inside the lung airways due to P. aeruginosa, morphology similar to Klebsiella and UPEC (IBCs) [94]. The biofilm formation ability could be evolutionary adaptation of pathogens that enable the bacteria to persist within the host cell. All these findings represent the formation of IBC, a process that enables the bacteria to rapidly expand inside the host cell and take part in bacterial persistence.
4. Postantibiotic period: treatment strategy for biofilm
Broad-spectrum antibiotics are the drug of choice for the treatment of bacterial infections. Conventional antibiotics act as either killing the bacterial cell (bactericidal) or inhibiting the cell division (bacteriostatic). Numerous evidence shows that the use of antibiotics extensively causes damage to the host microbiota, producing a condition where invading bacteria can prevail and enhance the selective pressure against drug resistance [95]. Furthermore, surgery proceeded by administering antibiotics is highly successful in order to minimize the infection prophylactically. In certain cases, the perfect treatment of choice for foreign material associated with biofilm infections is the removal of infectious device. In some cases like pacemakers, cardiac implants and implantable prostheses, device removal is difficult [37]. Biofilm formation nature of bacteria that make them recalcitrant against different antimicrobial drugs is a result of prolonged treatment. There is a need for the irradiation or complete removal of these kinds of pathogens. Antibiotic resistance is not only due to increased resistance markers transmitted within the bacterial biofilm community, but also due to high metal ion concentration, low pH, and the presence of persistent cells that are metabolically inactive and inactivate the antibiotics [31]. All these characteristics make bacterial biofilm more tolerant/resistant to antimicrobial drugs up to 1000-fold more when compared to planktonic bacterial cells [96]. Therefore, an alternative strategy must be investigated to combat the antibiotic resistant strains and make them vulnerable to antimicrobial drugs. Here below, we have mentioned some of the recent developments in strategies that are considered to prevent formation of biofilm by bactericidal mechanism or targeting distinct developmental stages of biofilm (Figure 2).
Figure 2.
Schematic diagram about the different stages in the development of biofilm and indicating the strategies to preventing and damaging the bacterial biofilm production at particular stages.
5. Bacterial killing strategies
5.1 Elimination of foreign material (indwelling devices) and abscess
There are studies that have reported that the presence of any foreign body (indwelling medical devices such as implants or prostheses or catheters) in low inoculums of Staphylococcus aureus (102 CFU/ml) in animal tissues was sufficient to form abscesses in the patients (95%) despite significant existence of leukocytes. In fact, this could be associated with the existence of any foreign material considerably intracellular bactericidal effects of body immune cells (leukocytes) and downregulated the mechanism of phagocytosis [97]. The polymorphonuclear leukocytes cannot perform well in the presence of any foreign body because it provides a surface ideal for the bacterial attachment. Therefore, the existence of any foreign material considerably increases the chances of bacterial biofilm formation. This leads to the pathogen becoming more persistent and resistant against conventional antibiotics. Thus, potential therapeutic strategy is required for the elimination of such type of bacterial biofilm formations. Certain precautionary measures could be employed, for instance, to replace the infected devices used for medical purposes in the patients with a new one. Otherwise, it would be hard to overcome the problem regardless of applying various effective antimicrobial drugs in response to fastidious pathogens. Changing dialysis catheter if it is infected by the pathogens is another measure that could be taken. When pathogen forms biomass on the catheter, it could be the source of bacterial colonization leading to bacteremia which may be caused by a deadly bacterial strain. For the cure of catheter-associated infections caused by bacterial biofilm formation, it is important to change the catheter infected with pathogens along with administration of antibiotic intravenously during a short time in order to eradicate the pathogen before it invades into the bloodstream. However, in some cases, it is hard to change the catheter temporarily; therefore, antimicrobial drugs and other alternative therapy may be the best option for the minimal release of pathogens from the infected site.
5.2 Phage therapy
An alternative approach to antibiotic treatment is phage therapy [98]. Phages are present in a wide range in the environment. It can be isolated easily and ubiquitous in nature. Their host ranges from specific to narrow, they are able to self-replicate, and therefore, a small dosage may be sufficient to disturb the host microorganisms. Furthermore, high mutation rate of phage facilitates adaptation as conforming bacterial host aggregate mutations to fix in a specific environment. Phage therapy has various advantages during lytic cycle phage that does not enter prophage cycle and rarely transfers or contains a virulence gene, thus causing destruction of bacterial cell rapidly. Many phages are associated with EPS degrading protein [99] or spread during stationary growth phase; these features allow to persist inside the bacterial biofilm [100].
5.3 Antimicrobial peptides
This is another alternative approach used for the improvement of new type of antimicrobial drug, usually produced by innate immune response mechanism [101]. Contrary to that, their mechanism of action and antimicrobial spectrum activity must be defined more accurately before applying as a therapeutic strategy. Cathelicidin, for instance, possesses most essential type of antibacterial peptides. The biofilm formation of multidrug-resistant Pseudomonas strains, isolated from cystic fibrosis (CF) patients, is reduced considerably by BMAP-28, BMAP-27, and BMAP-29 [102]. According to a recent study by Pompilio et al. [102], antimicrobial activity of tobramycin against multidrug-resistant strains is less than cathelicidin peptides. This study indicates that the multidrug-resistant strains are vulnerable to cathelicidins due to antibiofilm agents. Another important group that can be used to assess the inhibitory effects is called lytic peptides. These peptides assist in attachment of lipopolysaccharides (LPS) to the cell membrane of pathogen and cause cell membrane disruption. The study on Staphylococcus aureus indicated that in vitro formation of biofilm is prohibited by the lytic peptide (PTP-7) and easily penetrates the bacterial biofilm causing death of the bacteria at a rate of 99.9%. This peptide has the capacity to bear extreme acidic environment and inhibit the biofilm formation of Staphylococcus aureus [103].
5.4 Silver nanoparticles
Many researchers have done research on the antimicrobial property of silver nanoparticles. Fey [37] found that the silver nanoparticles are the best alternative strategy to combat the bacterial biofilms. For example, antimicrobial agents (silver nanoparticles) have been incorporated with medical devices and have showed to inhibit the device-associated bacterial biofilms. Silver was frequently used as an antimicrobial agent for different pathogens over a 100 years; for instance, during World War 1, it was extensively used to sterilize the wound infections [104]. The antimicrobial activity of silver nanoparticles depends on the positively charged ions of metal and electrostatic interactions between negatively charged cell membrane of bacteria [105]. The thiol group in silver is the main cause of death in bacteria that play an important role in the inactivation of enzyme [106]. This is the reason why silver nanoparticles are increasingly used in response to various bacterial infections. The antimicrobial agents contain different properties such as high aspect ratios, nonimmunogenic, biocompatible, nonbiodegradable, ultralight weight, and easy cell membrane penetration. Due to such remarkable properties, we can apply silver nanoparticles in various applications such as infection therapy, gene therapy, and as antioxidants. The size of silver nanoparticles is typically smaller than 100 nm. The mechanism of action of silver nanoparticle is to interrupt the cell membrane of bacteria, generate the reactive oxygen species (ROS), interrupt the metabolic pathway, prevent the replication of DNA, disrupt the bacterial electron transport chain (ETC) [106], and release the toxic ions outside the bacterial cells that lead to the death of bacteria. There are large numbers of studies conducted regarding toxicity mechanism of silver nanoparticles in rabbits. There is a study that showed that silver nanoparticles inhibited bacterial biofilm formation against Staphylococcus aureus, without accumulating inside the host tissue [106, 107].
5.5 Polysaccharides
Bacterial cell-to-cell interaction mediated by the exopolysaccharides is a serious threat to the formation of biofilm and stabilization. Mutants incapable to export or synthesize such exopolysaccharides are usually deficient in the formation of biofilm and adherence and hence are extremely sensitive to killing through host immune defenses and antimicrobial drugs [108]. Recent studies showed that certain bacterial exopolysaccharides destabilize or prevent biofilm formation by some pathogenic species. For instance, the existence of Pseudomonas aeruginosa prevented biofilm formation of S. epidermidis in in vitro experiments [109]. Polysaccharides along with nonbactericidal antibiofilm characteristics have been separated from acellular biofilm (or biomass) extracts of various species [108]. The antibiofilm properties of Pseudomonas aeruginosa have the ability to act as signaling molecules that effect the expression of genes in susceptible pathogens, change the physical features of isolated bacterial cells, and prevent the protein-carbohydrate interactions. Most polysaccharides with antibiofilm properties allow a broad-spectrum inhibition of biofilm, while some are proficient of scattering preformed biofilms. So far, there are evidence suggests that polysaccharide with antibiofilm features acts as a surfactant molecule that alters the physical properties of abiotic surfaces and bacterial cells. Some results also show that polysaccharides might modulate the expression of genes of the recipient pathogenic bacteria by acting as signaling molecules [110]. Another potential mode of action of polysaccharide is to prevent competitively the multivalent protein-carbohydrate interactions [66]. As a result, polysaccharides with antibiofilm properties might block tip adhesins of pili and fimbriae, or block sugar or lectin-binding proteins that are present on the outer surface of pathogens. In pathogen P. aeruginosa, for instance, lectin-dependent adhesion to human cell is proficiently repressed by galactomannans [111]. This kind of polysaccharides that inhibit the biofilm could be a prominent strategy appropriate for the prevention of bacterial infections. Some scientist showed that antibiofilm polysaccharides can be used as an adjuvant because of enhancing antibiotic drug functions [108].
5.6 Interference with signal transference
Many studies have been carried out on biofilm inhibition caused by interruption of the pathogen signaling cascades. This is possible provided that the two-component systems in bacteria establish a dominant means of translating and intercepting the environmental changes. Signal transduction inhibition system plays a critical role in response to antimicrobial therapy because of this type of signaling cascade interruption. Not only does it kill the pathogen, but it also interferes with the gene expression. Two-component system (QseBC) is the best alternative candidate for targeting the drugs, particularly in Gram-negative biofilm-forming pathogens [112]. QseC/QseB establishes a significant association between the bacterial environmental signaling and the host stress response. The pathogen (E. coli) responds to autoinducer-3 in the intestine that is formed by the human stress hormones (such as epinephrine and norepinephrine) and gut flora. The cascade of signaling transduction comprises chemotaxis by activation of QseC and by using the serine receptor Tsr. In the quest for novel antimicrobial drugs and therapeutic targets, two-component system (QseBC) can play an important role to inhibit biofilm formation by blocking the binding of epinephrine or norepinephrine to QseC, as a result to reduce QseB/QseC signaling and decrease virulence and motility [113]. Studies have also suggested that the removal of QseC in EHEC and UPEC causes an excessive activation of response regulator QseB, owing to particular QseC phosphatase activity required for deactivation of QseB. The optimal strategy behind targeting the phosphate activity is to interfere with common gene expression in QseC containing pathogens [47]. Some other studies focused on the FsrATC/FsrA inhibitors in E. faecalis. The expression of gelE-sprE and FsrBDC control by the FsrC/FsrA leads to increase in the production of serine protease and gelatinase, both are crucial for the proper eDNA production [71].
5.7 Antimatrix agents
Apart from that, extracellular matrix with disrupting components is also very important to target the bacterial aggregates. Various observations exploited the inhibiting enzymes potentially involved in the modification or synthesis of cell wall-secreted or associated with EPS components. In these studies, use of engineered or naturally occurring enzyme and use of phage therapy as an enzyme delivery vehicle or to interrupt with matrix integrity by taking benefits from metal chelators have been recommended.
5.8 Chelating agents
Metal cations such as iron, magnesium, and calcium have been associated with stabilizing the matrix integrity [114]. Chelating agents indicated to cause interruption in the bacterial cell membrane stability besides disrupting the bacterial biomass structure [39]. In vitro study showed that biofilm formation was inhibited in various Staphylococcus species by sodium citrate [115]. Furthermore, eradication of bacterial biofilms in in vitro experiments is also facilitated by tetrasodium EDTA, while disodium EDTA only reduced the bacterial biofilm formations in P. aeruginosa and Staphylococcus species [116]. Current reports suggested that the solution of minocycline-EDTA was used to inhibit indwelling catheter-associated infections especially in children. There were no adverse side effects observed in patients treated with the solution of minocycline-EDTA but only a limited number (21%) of untreated group (control) developed infections [117]. Moreover, in hemodialysis patients, catheter-associated bloodstream infections were observed after applying minocycline-EDTA [118].
5.9 Enzyme
The main mechanism of active dispersal of bacterial biofilm is through the formation of extracellular enzymes (proteins) that act on several structural components (such as exopolysaccharides, surface proteins, and extracellular DNA) of the extracellular polymeric substances. These enzymes play an important role in the cell separation from the bacterial biofilm colonies and facilitate their planktonic discharge into the environment [119]. Through purifying and isolating these enzymes, therapist can apparently add them to preformed bacterial biofilms exogenously at raised concentrations, in order to make biofilm-associated bacteria more susceptible to antimicrobials/antibiotics and to achieve interventional dispersal of biofilms. For this purpose, several classes of enzymes (specifically proteases, glycoside hydrolases, and deoxyribonucleases) have been explored for the eradication of bacterial biofilms [119]. The enzymes dispersin-B and DNase-I have gained greater attention as possible antibiofilm agents, especially in response to Gram-positive bacteria. The DNase effect depends on its capability to interrupt the eDNA that is established within the bacterial biomass structure [73]. The treatment of DNase prevents biofilm formation in Enterococcus and Staphylococcus and dispersed bacterial biofilm [73]. For the treatment of patients with cystic fibrosis (CF), a recombinant enzyme (pulmozyme) is used in some cases [37]. However, treatment with dispersin-B represented to be more effective in response to S. aureus and S. epidermidis [77]. In vitro studies indicated that engineered dispersin-B used bacteriophage machinery in order to replicate during the stationary phase of cell growth, hence causing disruption of complete E. coli biofilms [120].
6. Conclusion
Currently, the removal of bacterial biofilm is the most challenging task for the clinicians and microbiologists. Antibiotics are not the best choice for the treatment of infections caused by bacteria forming biofilm. Biofilm formation allows the pathogen to adhere to the host surface under extreme condition and is resistant against a wide range of antibiotics. The choice of drug depends on the characteristics of the biofilm such as composition, age, solidity, and type of pathogens. These are the major components influencing the microbial susceptibility. As the bacterial biofilm matures, it enhances the accumulation of exopolymeric substance (EPS), attaches with the oxygen and nutrient gradients that effect bacterial growth rates and metabolism of cells, becomes impermeable, and reduces the activity of antimicrobial agents. This leads to resistance to most antibiotic regime. Therefore, novel potential therapeutic strategies should be considered to curb bacterial biofilm formation at specific stage without harming the pathogen. Antiadhesion and antimatrix agents are exciting strategies that may be used pending further investigation.
List of abbreviations
EPS
extracellular polymeric substance
DNS
deoxyribonuclease
CBP
carbohydrate-binding protein
DNA
deoxyribonucleic acid
CUP
chaperone-usher pathway
UPEC
uropathogenic E. coli
PGA
polyglucosamine
SCV
small colony variants
eDNA
environmental deoxyribonucleic acid
PQS
Pseudomonas quinolone signal
c-di-GMP
cyclic di-GMP
AL
alginate lyase
BS
Bacillus subtilis
TLR-4
toll-like receptor-4
IBC
intracellular bacterial communities
UTIs
urinary tract infections
SEM
scanning electron microscope
TCA
tricarboxylic acid
qPCR
quantitative polymerase chain reaction
HAIs
hospital-acquired infections
CFU
colony forming unit
MDR
multidrug resistant
LPS
lipopolysaccharides
ETC
electron transport chain
ROS
reactive oxygen species
EHEC
enterohemorrhagic E. coli
EDTA
ethylene-diamine-tetra-acetic acid
CF
cystic fibrosis
\n',keywords:"biofilm, antibiotic resistant, distribution, control, therapeutic strategy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64267.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64267.xml",downloadPdfUrl:"/chapter/pdf-download/64267",previewPdfUrl:"/chapter/pdf-preview/64267",totalDownloads:563,totalViews:186,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"April 29th 2018",dateReviewed:"July 16th 2018",datePrePublished:"November 5th 2018",datePublished:"April 3rd 2019",dateFinished:null,readingETA:"0",abstract:"Bacteria have developed the capability to produce structured communities (or cluster of cells) via adherence to surface to form biofilms that facilitate or prolong their survival under extreme environmental condition. Bacterial biomass adheres to inanimate and biotic surfaces in the hospital setting as well as in the environment. In the healthcare system, the biofilm formation on medical devices allows bacteria to sustain as a reservoir and becomes more resistant to antimicrobial agents. However, biofilm formation facilitates pathogens to sabotage the host defenses that are linked to long-term retention within the host cell. Therefore, in this review, we provide some steps leading to the formation of biofilm within the host and on inanimate surfaces, also emphasizing various medically significant pathogens and debate current developments on novel approaches that aimed to prevent biofilm formations and its dispersion to patients.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64267",risUrl:"/chapter/ris/64267",book:{slug:"antimicrobials-antibiotic-resistance-antibiofilm-strategies-and-activity-methods"},signatures:"Mansab Ali Saleemi, Navindra Kumari Palanisamy and Eng Hwa Wong",authors:[{id:"256712",title:"Ph.D.",name:"Eng Hwa",middleName:null,surname:"Wong",fullName:"Eng Hwa Wong",slug:"eng-hwa-wong",email:"enghwa.wong@taylors.edu.my",position:null,institution:null},{id:"264554",title:"Ph.D. Student",name:"Mansab",middleName:"Ali",surname:"Saleemi",fullName:"Mansab Saleemi",slug:"mansab-saleemi",email:"mansabsaleemi@gmail.com",position:null,institution:null},{id:"264555",title:"Dr.",name:"Navindra Kumari",middleName:null,surname:"Palanisamy",fullName:"Navindra Kumari Palanisamy",slug:"navindra-kumari-palanisamy",email:"navindra@salam.uitm.edu.my",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Extracellular formation of biofilm",level:"1"},{id:"sec_2_2",title:"2.1 Bacterial attachment on surfaces and what does make it adhere to object surface?",level:"2"},{id:"sec_3_2",title:"2.2 Maturation of biofilm",level:"2"},{id:"sec_4_2",title:"2.3 Matrix escape mechanisms",level:"2"},{id:"sec_6",title:"3. Bacterial intracellular biofilms",level:"1"},{id:"sec_7",title:"4. Postantibiotic period: treatment strategy for biofilm",level:"1"},{id:"sec_8",title:"5. Bacterial killing strategies",level:"1"},{id:"sec_8_2",title:"5.1 Elimination of foreign material (indwelling devices) and abscess",level:"2"},{id:"sec_9_2",title:"5.2 Phage therapy",level:"2"},{id:"sec_10_2",title:"5.3 Antimicrobial peptides",level:"2"},{id:"sec_11_2",title:"5.4 Silver nanoparticles",level:"2"},{id:"sec_12_2",title:"5.5 Polysaccharides",level:"2"},{id:"sec_13_2",title:"5.6 Interference with signal transference",level:"2"},{id:"sec_14_2",title:"5.7 Antimatrix agents",level:"2"},{id:"sec_15_2",title:"5.8 Chelating agents",level:"2"},{id:"sec_16_2",title:"5.9 Enzyme",level:"2"},{id:"sec_18",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: From the natural environment to infectious diseases. Nature Reviews. Microbiology. 2004;2:95-108'},{id:"B2",body:'Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: A common cause of persistent infections. 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QseBC controls flagellar motility, fimbrial hemagglutination and intracellular virulence in fish pathogen Edwardsiella tarda. Fish & Shellfish Immunology. 2011;30:944-953'},{id:"B113",body:'Prüß BM. Involvement of Two-Component Signaling on Bacterial Motility and Biofilm Development. Journal of Bacteriology. 2017;199(18):e00259-e00217'},{id:"B114",body:'Raad II, Fang X, Keutgen XM, Jiang Y, Sherertz R, Hachem R. The role of chelators in preventing biofilm formation and catheter-related bloodstream infections. Current Opinion in Infectious Diseases. 2008;21:385-392'},{id:"B115",body:'Shanks RM, Sargent JL, Martinez RM, Graber ML, O’Toole GA. Catheter lock solutions influence staphylococcal biofilm formation on abiotic surfaces. Nephrology, Dialysis, Transplantation. 2006;21:2247-2255'},{id:"B116",body:'Bookstaver PB, Williamson JC, Tucker BK, Raad II, Sherertz RJ. Activity of novel antibiotic lock solutions in a model against isolates of catheter-related bloodstream infections. The Annals of Pharmacotherapy. 2009;43:210-219'},{id:"B117",body:'Chatzinikolaou I, Zipf TF, Hanna H, Umphrey J, Roberts WM, Sherertz R, et al. Minocycline-ethylene-diaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer. Clinical Infectious Diseases. 2003;36:116-119'},{id:"B118",body:'Bleyer AJ, Mason L, Russell G, Raad II, Sherertz RJ. A randomized, controlled trial of a new vascular catheter flush solution (minocycline-EDTA) in temporary hemodialysis access. Infection Control and Hospital Epidemiology. 2005;26:520-524'},{id:"B119",body:'Fleming D, Rumbaugh KP. Approaches to dispersing medical biofilm. Microorganisms. 2017;5:15. DOI: 10.3390/microorganisms5020015'},{id:"B120",body:'Lu TK, Collins JJ. Dispersing biofilms with engineered enzymatic bacteriophage. Proceedings of the National Academy of Sciences. 2007;104:11197-11202'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Mansab Ali Saleemi",address:null,affiliation:'
School of Biosciences, Taylor’s University Lakeside Campus, Malaysia
School of Medicine, Taylor’s University Lakeside Campus, Malaysia
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1. Introduction
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Bovine mastitis is one of the most important bacterial diseases of dairy cattle throughout the world. Mastitis is responsible for major economic losses to the dairy producer and milk processing industry resulting from reduced milk production, alterations in milk composition, discarded milk, increased replacement costs, extra labor, treatment costs, and veterinary services [1]. Annual economic losses due to bovine mastitis are estimated to be $2 billion in the United States [2], $400 million in Canada (Canadian Bovine Mastitis and Milk Quality Research Network-CBMQRN), and $130 million in Australia [3]. Many factors including host, pathogen, and environmental factors influence the development of mastitis; however, inflammation of the mammary gland is usually a consequence of adhesion, invasion, and colonization of the mammary gland by one or more contagious (Staphylococcus aureus, Streptocococcus agalactiae, Corynebacterium bovis, Mycoplasmsa bovis, etc.) or environmental (coliform bacteria, environmental Streptococcus spp. and some coagulase negative Staphylococcus spp., many other minor pathogens) mastitis pathogens.
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2. Etiology of mastitis
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Over 135 various microorganisms have been identified from bovine mastitis. The most common bovine mastitis pathogens are classified as contagious and environmental mastitis pathogens [4]. This classification depends upon their distribution in their natural habitat and mode of transmission from their natural habitat to the mammary glands of dairy cows [5]. It is important to mention that all pathogens lists as environmental or contagious may not be strictly environmental or strictly contagious; some of them may transmit both ways. Environmental mastitis pathogens exist in the cow’s environment, and they can cause infection at any time. Environmental mastitis pathogens are difficult to control because they are in the environment of dairy cows and can transmit to the mammary glands at any time, whereas contagious mastitis pathogens exist in the infected udder or on the teat skin and transmit from infected to non-infected udder during milking by milker’s hand or milking machine liners. Environmental mastitis pathogens include a wide range of organisms, including coliform bacteria (Escherichia coli, Klebsiella spp., Enterobacter spp., and Citrobacter spp), environmental Streptococcus spp. (Streptococcus uberis, Streptococcus dysgalactiae, Streptococcus equi, Streptococcus zooepidemicus, Streptococcus equinus, Streptococcus canis, Streptococcus parauberis, and others), Trueperella pyogenes, which was previously called Arcanobacterium pyogenes or Corynebacterium pyogenes and environmental coagulase-negative Staphylococcus species (CNS) (S. chromogenes, S. simulans, S. epidermidis, S. xylosus, S. haemolyticus, S. warneri, S. sciuri, S. lugdunensis, S. caprae, S. saccharolyticus, and others) [4, 6, 7, 8, 9] and others such as Pseudomonas, Proteus, Serratia, Aerococcus, Listeria, Yeast and Prototheca that are increasingly found as mastitis-causing pathogens on some farms [10, 11].
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Contagious mastitis pathogens primarily exist in the infected mammary glands or on the cow’s teat skin and transmit from infected to non-infected mammary glands during milking by milker’s hand or milking machine liners. Mycoplasma spp. may spread from cow to cow through aerosol transmission and invade the udder subsequent to bacteremia. The most frequent contagious mastitis pathogens are coagulase-positive Staphylococcus aureus, Streptococcus agalactiae, Mycoplasma bovis, and Corynebacterium bovis [11, 12]. The prevalence of mastitis caused by these different mastitis pathogens varies depending on herd management practices, geographical location, and other environmental conditions [13]. These different causative agents of mastitis have a multitude of virulence factors that make treatment and prevention of mastitis difficult.
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2.1 Environmental mastitis pathogens
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It is important to mention that all environmental mastitis pathogens may not be strictly environmental, and some of them may transmit both ways (contagious and environmental). However, the vast majority of these organisms are in the environment of dairy cows, and they transmit from these environmental sources to the udder of a cow at any time of the lactation cycle.
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2.1.1 Streptococcus uberis mastitis
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\nStreptococcus uberis is one of the environmental mastitis pathogens that accounts for a significant proportion of subclinical and clinical mastitis in lactating and non-lactating cows and heifers [14]. This organism is commonly found in the bedding material, which facilitates infection of mammary glands at any time [15]. Some report also indicated the possibility of contagious transmission of Streptococcus uberis [16].
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\nS. uberis has various mechanisms of virulence that increases the chances of this organism establishing infection. These include a capsule, which evades phagocytosis, adherence to, and invasion into mammary epithelial cells [17, 18]. S. uberis adheres to epithelial cells using different mechanisms, including the formation of pedestals [19] and bridge formation through Streptococcus uberis adhesion molecule (SUAM) and lactoferrin [20, 21, 22]. This attachment is specific and mediated through a bridge formation between Streptococcus uberis adhesion molecule (SUAM) [23, 24] on S. uberis surface and lactoferrin, which is in the mammary secretion and has a receptor on the mammary epithelial surface [20, 22]. This interaction creates a molecular bridge that enhances S. uberis adherence to and internalization into mammary epithelial cells most likely via caveolae-dependent endocytosis and potentially allows S. uberis to evade host defense mechanisms [22, 24]. These factors increase the pathogenicity of S. uberis to cause mastitis. The sua gene is conserved among strains of S. uberis isolated from geographically diverse areas [9, 13], and a sua deletion mutant of S. uberis is defective in adherence to and internalization into mammary epithelial cells [14].
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2.1.2 Coagulase-negative Staphylococcus species (CNS)
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More recently, coagulase-negative Staphylococcus species (CNS) such as S. chromogenes, S. simulans, S. xylosus, S. haemolyticus, S. hyicus, and S. epidermidis are increasingly isolated from bovine milk [7, 25, 26, 27] with S. chromogenes being the most increasingly diagnosed species as a cause of subclinical mastitis. Staphylococcus chromogenes [28] and other CNS [4, 8] have been shown to cause subclinical infections in dairy cows that reduce the prevalence of contagious mastitis pathogens.
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\nStaphylococcus chromogenes is most commonly isolated from mammary secretions rather than from the environment itself [8, 29]. S. chromogenes consistently isolated from the cow’s udder and teat skin [30], and some studies showed that it causes long-lasting, persistent subclinical infections [26]. The CNS causes high somatic cell counts in milk on some dairy farms [29, 31]. Woodward et al. [32] evaluated the normal teat skin flora and found that 25% of the isolates exhibited the ability to prevent the growth of some mastitis pathogens. An in vitro study conducted on S. chromogenes showed that this organism could inhibit the growth of major mastitis-causing pathogens such as Staph. aureus, Strep. dysgalactiae, and Strep. uberis [28]. In a study conducted on conventional and organic Canadian dairy farms, CNS were found in 20% of the clinical samples [33]. Recently, mastitis caused by CNS increasingly became more problematic in dairy herds [30, 34, 35, 36]. However, mastitis caused by CNS is less severe compared to mastitis caused by Staphylococcus aureus [26].
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2.1.3 Coliform mastitis
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Coliform bacteria such as Escherichia, Klebsiella, and Enterobacter are a common cause of mastitis in dairy cows [37]. The most common species, isolated in more than 80% of cases of coliform mastitis, is Escherichia coli [38, 39]. E. coli usually infects the mammary glands during the dry period and progresses to inflammation and clinical mastitis during the early lactation with local and sometimes severe systemic clinical manifestations. Some reports indicated that the severity of E. coli mastitis is mainly determined by cow factors rather than by virulence factors of E. coli [40]. However, recent molecular and genetic studies showed that the pathogenicity of E. coli is entirely dependent on the FecA protein that enables E. coli to actively uptake iron from ferric-citrate in the mammary gland [41]. The severity of the clinical mastitis and peak E. coli counts in mammary secretions are positively correlated. Intramammary infection with E. coli induced expression and release of pro-inflammatory cytokines [42, 43]. Recently, it has been shown with mouse mastitis models that IL-17A and Th17 cells are instrumental in the defense against E. coli intramammary infection [44, 45]. However, the role of IL-17 in bovine E. coli mastitis is not well defined. The result of recent vaccine efficacy study against E. coli mastitis suggested that cell-mediated immune response has more protective effect than humoral response [46]. However, the cytokine signaling pathways that lead to efficient bacterial clearance are not clearly defined.
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2.2 Contagious mastitis pathogens
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2.2.1 Coagulase-positive Staphylococcus aureus\n
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Coagulase-positive Staphylococcus aureus is one of the most common contagious mastitis pathogens in dairy cows, with an estimated incidence rate of 43–74% [47, 48]. Staphylococcus aureus is grouped under the family Staphylococcaceae and genus Staphylococcus. It is a gram-positive, catalase and coagulase-positive, non-spore forming, oxidase negative, non-motile, cluster-forming, and facultative anaerobe [49]. The coagulase test is not an absolute test for the confirmation of the diagnosis of S. aureus from the cases of bovine mastitis, but more than 95% of all coagulase-positive staphylococci from bovine mastitis belong to S. aureus [50]. Other coagulase-positive species include S. aureus subsp. anaerobius causes lesion in sheep; S. pseudintermedius causes pyoderma, pustular dermatitis, pyometra, otitis externa, and other infections in dogs and cats; S. schleiferi subsp. coagulans causes otitis externa (inflammation of the external ear canal) in dogs; S. hyicus is coagulase variable (some strains are positive and some others are negative), species that causes mastitis in dairy cows, exudative epidermitis (greasy pig disease) in pigs; and S. delphini causes purulent cutaneous lesions in dolphins.
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\nS. aureus can infect many host species, including humans. In humans, S. aureus causes a wide variety of illnesses ranging from mild skin infection to a life-threatening systemic infection. It has been reported that certain strains of S. aureus with specific tissue tropism can be adapted to infect specific tissue such as the mammary gland [51]. Furthermore, a study by McMillan [52] showed distinct lineages of S. aureus in bovine, ovine, and caprine species. S. aureus strains can be host specific, meaning that they are found more commonly in a specific species [51]. Some studies showed that S. aureus that causes mastitis belong to certain dominant clones, which are frequently responsible for clinical and subclinical mastitis in a herd at certain geographic areas, indicating that the control measures may need to be directed against specific clones in a given area [53, 54, 55]. However, because S. aureus is such a big problem in human health, cross-infection has been an important research topic. Several studies have reported cases of cross-infection in several different species [56, 57, 58]. In the dairy industry, there have been reports of human origin methicillin-resistant S. aureus infecting bovine mammary glands [59, 60]. These studies add to the unease that strains can gain new mutations or virulence factors and adapt to cross the interspecies boundary relatively rapidly [61].
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Although the incidence of S. aureus mastitis can be reduced with hygienic milking practices and a good management system, it is still a major problem for dairy farms, with a prevalence of 66% among farms tested in the United States [62]. The prevalence of S. aureus mastitis varies from farm to farm because of variation in hygienic milking practices and overall farm management differences on the application of control measures for contagious mastitis pathogens. Good hygiene in the milking parlor can significantly reduce the occurrence of new S. aureus mastitis in the herd, but it does not remove existing cases within a herd [63]. Neave et al. concluded that it is nearly impractical to keep all udder quarters of dairy cows free of all pathogens at all times. Since this early observation by Neave et al. [63], many studies have confirmed that management practices can reduce new cases of intramammary infection (IMI) [9, 64] but cannot eliminate existing infections. In the United States, the prevalence of clinical and subclinical S. aureus mastitis ranged from 10 to 45% [65] and 15 to 75%, respectively.
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2.2.1.1 Virulence factors of S. aureus\n
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\nStaphylococcus aureus has many virulence factors that can be grouped broadly into two major classes. These include (1) secretory factors which are surface localized structural components that serve as virulence factors and (2) secretory virulence factors which are produced by bacteria cells and secreted out of cells and act on different targets in the host body. Both non-secretory and secretory virulence factors together help this pathogen to evade the host’s defenses and colonize mammary glands.
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2.3 Non-secretory factors
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Some of surface localized structural components that serve as virulence factors include membrane-bound proteins, which include collagen-binding protein, fibrinogen-binding protein, elastin-binding protein, penicillin-binding protein, and lipoteichoic acid. Similarly, cell wall-bound factors such as peptidoglycan, lipoteichoic acid, teichoic acid, protein A, β-Lactamase, and proteases serve as non-secretory virulence factors. Other cell surface-associated virulence factors include exopolysaccharides, which comprises capsule, slime, and biofilm. Overall, S. aureus has over 24 surface proteins and 13 secreted proteins that are involved in immune evasion [66] and about 15–26 proteins for biofilm formation [67, 68].
\n
Surface proteins, such as staphylococcal protein A (SpA), clumping factors A and B (ClfA and ClfB) [69, 70, 71], fibrinogen-binding proteins [72], iron-regulated surface determinants (IsdA, IsdB, and IsdH) [69, 73], fibronectin-binding proteins A and B [74], biofilm associated protein (BAP) and exopolysaccharides (capsule, slime, and biofilms) [75, 76, 77, 78, 79], play roles in S. aureus adhesion to and invasion into host cells [80]. The BAP expression enhances biofilm production and the BAP gene is only found in S. aureus strain from bovine origin [81, 82, 83]. Evaluation of BAP gene of S. aureus from bovine and human isolates using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) showed that bovine and human isolates are not closely related [84]. Thus, some host-specific evolutionary factors may have been developed between both strain types.
\n
Biofilms are considered an important virulence factor in the pathogenesis of bovine S. aureus mastitis [77, 78]. Slime, an extracellular polysaccharide layer, acts as a barrier against phagocytosis and antimicrobials. It also helps with adhesion to a surface [85]. If a biofilm forms in a mammary gland, it will protect those bacteria from antimicrobials and the host’s immune system [77, 78]. In addition, once the biofilm matures and the immune attack has subsided, the biofilm can break open and allow reinfection of the mammary gland [86]. There are many contributors to biofilm production, such as polysaccharide intercellular adhesin (PIA) also known as poly-N-acetyl-β (1-6)-glucosamine (PNAG), MSCRAMMS, teichoic acids, and extracellular DNA (eDNA) [75, 76] that are known to help these bacteria cells to hold onto a surface [87]. Various proteins encoded by intercellular adhesion loci such as icaA, icaB, icaC, and icaD are involved in PIA production which in turn result in biofilm formation [75, 76]. Vasudevan et al. [88] evaluated the correlation of slime production and presence of the intercellular adhesion (ica) genes with biofilm production. These authors [88] found that all tested isolates were positive for icaA and icaD genes, and most tested isolates produce slime, but not all slime positives produced biofilms in vitro. Similarly, a study in Poland found that all isolates were positive for icaA and icaD [80] genes. While adhesion is promoted with biofilm production, the bap gene prevents the invasion of host cells [83]. Despite the presence of the ica gene strongly support biofilm production, the presence of the ica gene is not mandatory for biofilm production since S. aureus lacking ica gene can still produce biofilm through other microbial surface components recognizing adhesive matrix molecules (MSCRAM) and secreted proteins [89, 90].
\n
\n
\n
2.4 Secretory factors
\n
Some of the known secretory virulence factors are toxins which include staphylococcal enterotoxins, non-enteric exfoliative toxins, toxic shock syndrome toxin 1, leucocidin, and hemolysins (alpha, beta, delta, and gamma) [91, 92]. Similarly, enzymes such as coagulase, staphylokinase, DNAase, phosphatase, lipase, phospholipase, and hyaluronidase serve as virulence factors of S. aureus [93].
\n
\n
2.4.1 Hemolysins
\n
\nS. aureus isolates from bovine mastitis produce alpha (α), beta (β), gamma (γ), and delta (δ) hemolysins that cause hemolysis of red blood cells of the host [94] and all are antigenically distinct. α-hemolysin is a pore-forming toxin that binds to a disintegrin and metalloproteinase domain-containing protein-10 (ADAM10) receptor resulting in pore formation and cellular necrosis [95, 96]. It is also known to increase the inflammatory response and decrease macrophage function [97]. α-hemolysin damages the plasma membrane of the epithelial cell resulting in leakages of low-molecular-weight molecules from the cytosol and death of the cell [98]. It is produced by 20–50% of strains from bovine IMI [99]. A study reported that the α-hemolysin might be required for a cell to cell interaction during biofilm formation [100]. β-hemolysin hydrolyzes the sphingomyelin present in the plasma membrane resulting in increased permeability with progressive loss of cell surface charge [101]. It is produced by 75–100% of S. aureus strains from bovine IMI [99]. α-hemolysin expression requires specific growth conditions in vitro because its growth is inhibited by agar [102]. α-hemolysin producing strains cause complete hemolysis of sheep red blood cells, whereas β-hemolysin producing strains cause partial hemolysis within 24 h of incubation at 37°C [103]. Partial hemolysis caused by β-hemolysin becomes completely lysed after further storage at 4–15°C, which is also expressed as hot-cold lysis [104]. β-hemolysin producing strains are the most frequent isolates from animals [105]. δ-hemolysin causes complete hemolysis of red blood cells of wide range of species including human, rabbit, sheep, horse, rat, guinea pig, and some fish erythrocytes. δ-hemolysin migrates more slowly through agar than the α-hemolysin so the effect takes longer time to express. Double (α- and β-) hemolysin producing strains caused complete hemolysis in the middle with partial hemolysis on the peripheral area around each colony [105]. γ-hemolysin is produced by almost every strain of S. aureus, but γ-hemolysin is not identifiable on blood agar plates, due to the inhibitory effect of agar on toxin activity [106].
\n
\n
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2.4.2 Enterotoxins Enterotoxins
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These toxins are heat stable and can resist pasteurization. S. aureus produces staphylococcal enterotoxins A, B, C, D, E, G, H, I, and J–Q as well as toxic shock syndrome toxin 1 (tsst-1) [105, 107, 108]. Enterotoxins can get into the food chain through the consumption of contaminated food and cause food poisoning [109]. Staphylococcal enterotoxins tend to contaminate dairy products and cause foodborne illness [110, 111]. Staphylococcal enterotoxins G to Q (SEG–SEQ) are prevalent among S. aureus isolates from cases of bovine mastitis and are also implicated in the pathogenesis of mastitis. Some of these toxins are known to function as superantigens that cause increased immunological reactivity in the host [110]. Some studies showed that about 20% of S. aureus isolates from IMI produce toxic shock syndrome toxin-1 [109, 112]. Toxic shock syndrome toxin causes toxic shock syndrome and can be fatal [113]. Besides the superantigenic effect of enterotoxins, their role in the pathogenesis of mastitis is unknown. It may be specific to each strain or area based on selective pressures in the habitat [114]. Enterotoxin prevalence seems to vary between geographical regions. The strains producing enterotoxin C have been isolated relatively frequently from cases of bovine mastitis [108, 115, 116].
\n
Enterotoxins are believed to have a role in the development of mastitis since S. aureus isolates from cases of mastitis had a high prevalence of enterotoxins than isolates from milk of cows without mastitis [117, 118]; however, staphylococcal enterotoxins expressions are controlled by several regulatory elements [119] that respond to a variety of different micro-environmental stimuli and the exact mechanisms by which enterotoxins contribute to the development of mastitis are not clearly known and yet to be determined.
\n
In addition to specific virulence factors, Staphylococcus aureus also possesses different mechanisms or traits such as biofilm formation, adhesion to and invasion into mammary epithelial cells, and formation of small colony variant (SCV) that enable this pathogen to resist host defense mechanisms. The ability of S. aureus to invade mammary epithelial cells during mastitis plays a significant role in the pathogenesis of S. aureus. Internalized bacteria can hide from the host’s immune system inside the host cell and continue to multiply inside the host cell [120]. There may be many mechanisms that S. aureus uses to invade into host cells, and each mechanism can be strain dependent. S. aureus strains have a fibronectin-binding protein that can link to the fibronectin on the mammary epithelial cell surface. Fibronectin binding protein is thought to be a common way for the bacteria cells to invade bovine mammary epithelial cells. Fibronectin-binding protein-deficient strains cannot invade host cells [121]. The presence of a capsule prevents adherence to epithelial cells [122, 123].
\n
Adhesion is the first step in the formation of biofilm or the invasion of host cells, which protects the bacteria from the host immune system and facilitates chronic infection [124]. Adhesion is dependent on surface proteins called adhesins, which help the bacterium to recognize and attach to host cells. Staphylococci are coated with a wide variety of surface proteins that help them to adhere to host cells and extracellular matrix components. Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) of the host are the most common surface proteins that are involved in adhesion [124]. The ability to bind to host tissue or the host’s cell surface is a pivotal part of the bacteria’s pathogenicity because adhesion is typically the first step in the invasion and biofilm formation [125, 126].
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Adhesion to and invasion into epithelial cells [124], intracellular survival in macrophages [127], and epithelial cells allow them to avoid detection by the host immune system and resist treatment with antibiotics [120]. Due to its poor response to treatments, S. aureus infections often become chronic with a low cure rate [128]. Treatment of Staphylococcus aureus mastitis with cloxacillin cured only 25% of the clinical cases and 40% of subclinical cases in the study by Tyler and Baggot [129]. Staphylococcus aureus also has a known ability to form biofilms [77, 78, 86] and acquire antimicrobial-resistance genes via horizontal resistance gene transfer, which enables this bacterium to develop antimicrobial resistance [130, 131].
\n
The mode of transmission from infected mammary glands or colonized udder skin to healthy mammary glands is through contact during milking procedures with milker’s hand, towel, and milking machine [58]. S. aureus usually causes subclinical or chronic infections and is difficult to clear with antibiotic treatment [132].
\n
\n
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2.4.3 Streptococcus agalactiae\n
\n
The most important virulence factor of S. agalactiae is the capsular polysaccharide [133], which protects this bacterium from being engulfed by macrophages and subsequently phagocytosed [133]. Another virulence factor of S. agalactiae is the Rib protein, which confers resistance to proteases. Emaneini et al. [133] found that the Rib encoding gene (rib) was detected in 89% of the isolates from bovine origin. Streptococcus agalactiae causes persistent infections that are usually difficult to clear without antibiotic treatment [134]. Though Streptococcus agalactiae is highly contagious, it has good response to treatment with antibiotics, which makes it possible to eliminate from herds with current mastitis control measures [129]. Since the adoption of hygienic milking practices, the incidence of mastitis caused by S. agalactiae has dramatically decreased and is now rarely observed in dairy herds [135].
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2.4.4 Mycoplasma mastitis
\n
Mastitis caused by Mycoplasma spp. is a growing concern in the United States. It is believed that this organism has been underreported due to the difficulty of isolation by culture method [136]. The incidence of Mycoplasma mastitis varies across the globe, with a 3.2% prevalence rate in the United States that may increase to 14.4% in larger herd size of greater than 500 cows [47, 48, 62, 137]. A risk factor for Mycoplasma mastitis increase with herd size, and most of the Mycoplasma mastitis cases are subclinical infections with outbreaks linked to asymptomatic carriers [138]. Pathogenesis of most Mycoplasma spp. infection is characterized by adherence to and internalization into host cells resulting in colonization of the host with immune modulation without causing severe disease [138]. Mycoplasma species lack a cell wall, thus not sensitive to beta-lactam antibiotics, but showed sensitivity to non-beta-lactam antibiotics [139].
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3. Routes of entry of mastitis pathogens to the udder
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In general, it is believed that mastitis pathogens gain entrance to the udder through teat opening into the teat canal and from the teat canal into the intramammary area during the reverse flow of milk due to vacuum pressure fluctuation of the milking machine [9]. However, the detailed mechanism of mastitis pathogen colonization of the mammary gland may vary among species of bacteria and the virulence factors associated with particular strain in each species. An example of this is in some cases; it has been shown that E. coli can penetrate the teat canal without the reverse flow of milk [9]. Some of the major mastitis pathogens, such as E. coli [140], Staphylococcus aureus, and Streptococcus uberis [20, 21, 22] can adhere to and subsequently invade into the mammary epithelial cells. This adherence and subsequent invasion into mammary epithelial cells allow them to persist in the intracellular area as well as to escape the host immune defenses attack and action of antimicrobial drugs [120, 140, 141, 142, 143, 144]. Dogan et al. [145] compared E. coli strains known to cause chronic infections with strains known to cause acute infections and found that chronic strains were more invasive to the epithelial cells, leading to the difficulty in clearance and persistent infection compared to acute strains. S. aureus enters the mammary gland through the teat opening and subsequently multiply in the mammary gland where they may form biofilms, attach to, and internalize into the mammary epithelial cells causing inflammation of mammary glands characterized by swelling, degeneration of epithelial cells, and epithelial erosions and ulcers [146, 147].
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4. Clinical manifestation of mastitis
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Depending on clinical signs, mastitis can also be divided into clinical and subclinical mastitis. Clinical mastitis is characterized by visible inflammatory changes (abnormalities) in the mammary gland tissue such as redness, swelling, pain, increased heart, and abnormal changes in milk color (watery, bloody, and blood tinged) and consistency (clots or flakes) [9]. Clinical mastitis can be acute, peracute, subacute, or chronic. Acute mastitis is a very rapid inflammatory response characterized by systemic clinical signs which include fever, anorexia, shock, as well as local inflammatory changes in the mammary gland and milk. Peracute mastitis is manifested by a rapid onset of severe inflammation, pain, and systemic symptoms that resulted in a severely sick cow within a short period of time. Subacute mastitis is the most frequently seen form of clinical mastitis characterized by few local signs of mild inflammation in the udder and visible changes in milk such as small clots. Chronic mastitis is a long-term recurring, persistent case of mastitis that may show few symptoms of mastitis between repeated occasional flare-ups of the disease where signs are visible and can continue over periods of several months. Chronic mastitis often leads to irreversible damage to the udder from the repeated occurrences of the inflammation, and often these cows are culled.
\n
Subclinical mastitis is the inflammation of the mammary gland that does not create visible changes in the milk or the udder. Subclinical mastitis is an infection of mammary gland characterized by non-visible inflammatory changes such as a high somatic cell count coupled with shedding of causative bacteria through milk [9]. During this inflammatory process, the milk samples showed a rapid increase of somatic cells, characterized by increased number of neutrophils in the secretion [146, 148]. Despite increased recruitment of somatic cells into infected mammary glands, evidenced by an increased number of neutrophils, infection usually does not clear but became subclinical. Intramammary infections during early lactation may become acute clinical mastitis characterized by gangrene development due congestion and thrombosis (blockage) of blood supply to the tissue but most new infection during late lactation or dry period become acute or chronic mastitis [149, 150].
\n
The increase in somatic cell count during subclinical infections leads to a decrease in useful components in the milk, such as lactose and casein [151]. Lactose is the sugar found in milk, and casein is one of the major proteins in milk and decreases in these two components affect the quality and quantity of milk yield [9]. During mastitis, there is an increase in lipase and plasmin, which have a detrimental effect on the quantity and quality of milk due to the breakdown of milk fat and casein [9]. Subclinical infections can reduce milk production by 10–12% when just one-quarter is infected [152]. These subclinical infections cause some of the greatest unseen economic [20] losses because of their detrimental impact on production and milk quality without showing visible signs of infection [152].
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5. Risk factors for mastitis
\n
There are host-, pathogen-, and environmental-related risk factors that predispose dairy cows to mastitis. The host risk factors include age (parity), stage of lactation, somatic cell count, breed, the anatomy of the mammary glands/morphology of udder and teat (diameter of teat canal and conformation of the udder), and immune competence (immunity) [153] (Figure 1). The environmental risk factors include the proper functioning status of milking machine, udder trauma, sanitation, climate, nutrition, management, season, and housing condition [154] (Figure 1). The pathogen risk factors include type (bacteria, fungi, yeast, and algae), number (large number and small number), virulence (highly, moderate, or less virulent), frequency of exposure (dirty farm floor, dirty milking machine, and dirty teat drying towels frequently expose to pathogen; clean floor, clean milking machine, and clean teat drying towels less exposure to pathogens), ability to resist flushing out of the glands by milk (ability to adhere or attach to and invade or internalize into mammary epithelial cells), zoonotic (transmit from cow to human or vice versa) potential, and resistance to antimicrobials [4] (Figure 1). The warm, humid, and moist climate favors the growth of bacteria and increases the chances of intramammary infection (IMI) and mastitis development [154]. The incidence of mastitis varies from farm to farm due to the combined effects of these different factors that increase the risk of disease development.
\n
Figure 1.
Risk factors for mastitis. SA, Staphylococcus aureus; EC, Escherichia coli; SU, Streptococcus uberis; SCC, somatic cell count; AMR, antimicrobial resistance.
\n
Dairy cows are highly susceptible to IMI during the early dry period due to increased colonization of teat skin with bacteria. Bacterial colonization of teat increases during the early dry period because of an absence of hygienic milking practices including pre-milking washing and drying of teats [155], as well as pre- and post-milking teat dipping in antiseptic solutions [156, 157] that are known to reduce teat end colonization and infection. An udder infected during the early dry period usually manifests clinical mastitis during the transition period because of increased production of parturition inducing immunosuppressive hormones [158, 159], negative energy balance [160], and physical stress during calving [161].
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\n
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6. Role of mastitis on public health
\n
Mastitis is increasingly becoming a public health concern due to the ability of the causative bacterial pathogens and/or their products, such as enterotoxins, to enter the food supply and cause foodborne diseases [109, 162], especially through the consumption of raw milk [29] and undercooked meat of culled dairy cows due to chronic mastitis that are usually sold to the slaughter (abattoir) for meat consumption. The Center for Disease Control (CDC) estimated that roughly 48 million people in the United States a year become sick from foodborne diseases [163]. Foodborne pathogens have been detected in bulk tank milk in multiple studies [164, 165, 166, 167]. These authors found that the number of foodborne pathogens detected in bulk tank milk vary with location, management practices, hygiene, and number of animals on the farm [165]. Similarly, a study on bulk tank milk from east Tennessee and southwest Virginia by Rohrbach et al. [168] showed that 32.5% of the samples analyzed contained one or more foodborne pathogens. Even dairy producers who used proper hygienic milking practices, pre- and post-milking teat disinfectant and antibiotic dry cow therapy, had foodborne pathogens in their bulk tank milk [164]. The isolation of these foodborne pathogens from bulk tank milk samples across the United States demonstrate the threat that mastitis pathogens and zoonotic mastitis causing pathogens create on public health if raw milk is consumed or if these pathogens make it through processing.
\n
\n
\n
7. Conclusions
\n
Bovine mastitis is the most important multifactorial disease of dairy cattle throughout the world. Mastitis is responsible for huge economic losses to the dairy producers and milk processing industry due to reduced milk production, alterations in milk composition, discarded milk, increased replacement costs, extra labor, treatment costs, and veterinary services. Many factors including pathogen, host, and environment can influence the development of mastitis. Mastitis, the inflammation of the mammary gland is usually a consequence of adhesion, invasion, and colonization of the mammary gland by one or more mastitis pathogens such as Staphylococcus aureus, Streptococcus uberis, and Escherichia coli.
\n
\n\n',keywords:"mastitis, bovine, Staphylococcus, Streptococcus",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73116.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73116.xml",downloadPdfUrl:"/chapter/pdf-download/73116",previewPdfUrl:"/chapter/pdf-preview/73116",totalDownloads:220,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 15th 2019",dateReviewed:"July 27th 2020",datePrePublished:"September 2nd 2020",datePublished:"January 20th 2021",dateFinished:"September 2nd 2020",readingETA:"0",abstract:"Bovine mastitis is one of the most important bacterial diseases of dairy cattle throughout the world. Mastitis is responsible for great economic losses to the dairy producer and to the milk processing industry resulting from reduced milk production, alterations in milk composition, discarded milk, increased replacement costs, extra labor, treatment costs, and veterinary services. Economic losses due to bovine mastitis are estimated to be $2 billion in the United States, $400 million in Canada (Canadian Bovine Mastitis and Milk Quality Research Network-CBMQRN) and $130 million in Australia per year. Many factors can influence the development of mastitis; however, inflammation of the mammary gland is usually a consequence of adhesion, invasion, and colonization of the mammary gland by one or more mastitis pathogens such as Staphylococcus aureus, Streptococcus uberis, and Escherichia coli.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73116",risUrl:"/chapter/ris/73116",signatures:"Oudessa Kerro Dego",book:{id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,fullTitle:"Animal Reproduction in Veterinary Medicine",slug:"animal-reproduction-in-veterinary-medicine",publishedDate:"January 20th 2021",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",fullName:"Oudessa Kerro Dego",slug:"oudessa-kerro-dego",email:"okerrode@utk.edu",position:null,institution:{name:"University of Tennessee at Knoxville",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Etiology of mastitis",level:"1"},{id:"sec_2_2",title:"2.1 Environmental mastitis pathogens",level:"2"},{id:"sec_2_3",title:"2.1.1 Streptococcus uberis mastitis",level:"3"},{id:"sec_3_3",title:"2.1.2 Coagulase-negative Staphylococcus species (CNS)",level:"3"},{id:"sec_4_3",title:"2.1.3 Coliform mastitis",level:"3"},{id:"sec_6_2",title:"2.2 Contagious mastitis pathogens",level:"2"},{id:"sec_6_3",title:"2.2.1 Coagulase-positive Staphylococcus aureus\n",level:"3"},{id:"sec_7_3",title:"2.2.1.1 Virulence factors of S. aureus\n",level:"3"},{id:"sec_9_2",title:"2.3 Non-secretory factors",level:"2"},{id:"sec_10_2",title:"2.4 Secretory factors",level:"2"},{id:"sec_10_3",title:"2.4.1 Hemolysins",level:"3"},{id:"sec_11_3",title:"2.4.2 Enterotoxins Enterotoxins",level:"3"},{id:"sec_12_3",title:"2.4.3 Streptococcus agalactiae\n",level:"3"},{id:"sec_13_3",title:"2.4.4 Mycoplasma mastitis",level:"3"},{id:"sec_16",title:"3. Routes of entry of mastitis pathogens to the udder",level:"1"},{id:"sec_17",title:"4. Clinical manifestation of mastitis",level:"1"},{id:"sec_18",title:"5. Risk factors for mastitis",level:"1"},{id:"sec_19",title:"6. Role of mastitis on public health",level:"1"},{id:"sec_20",title:"7. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'\nPetrovski K, Trajcev M, Buneski G. A review of the factors affecting the costs of bovine mastitis. Journal of the South African Veterinary Association. 2006;77:52-60\n'},{id:"B2",body:'\nNMC. The Cost of Mastitis: Dairy Insight Research 2005/2006: Final report. 2005\n'},{id:"B3",body:'\nIsmail ZB. Mastitis vaccines in dairy cows: Recent developments and recommendations of application. Veterinary world. 2017;10:1057\n'},{id:"B4",body:'\nBradley AJ. Bovine mastitis: An evolving disease. The Veterinary Journal. 2002;164:116-128\n'},{id:"B5",body:'\nCalvinho LF, Oliver SP. Invasion and persistence of streptococcus dysgalactiae within bovine mammary epithelial cells. Journal of Dairy Science. 1998;81:678-686\n'},{id:"B6",body:'\nBecker K, Heilmann C, Peters G. Coagulase-negative staphylococci. Clinical Microbiology Reviews. 2014;27:870-926\n'},{id:"B7",body:'\nDe Vliegher S, Fox LK, Piepers S, McDougall S, Barkema HW. Invited review: Mastitis in dairy heifers: Nature of the disease, potential impact, prevention, and control. Journal of Dairy Science. 2012;95:1025-1040\n'},{id:"B8",body:'\nPiessens V, Van Coillie E, Verbist B, Supre K, Braem G, Van Nuffel A, et al. Distribution of coagulase-negative staphylococcus species from milk and environment of dairy cows differs between herds. Journal of Dairy Science. 2011;94:2933-2944\n'},{id:"B9",body:'\nBlowey RW. Mastitis Control in Dairy Herds. 2nd ed. Cambridge, Mass, MA: CABI; 2010\n'},{id:"B10",body:'\nCameron M, Saab M, Heider L, McClure JT, Rodriguez-Lecompte JC, Sanchez J. Antimicrobial susceptibility patterns of environmental streptococci recovered from bovine milk samples in the maritime provinces of Canada. Front Vet Sci. 2016;3:79\n'},{id:"B11",body:'\nBobbo T, Ruegg PL, Stocco G, Fiore E, Gianesella M, Morgante M, et al. Associations between pathogen-specific cases of subclinical mastitis and milk yield, quality, protein composition, and cheese-making traits in dairy cows. Journal of Dairy Science. 2017;100:4868-4883\n'},{id:"B12",body:'\nBarkema HW, Green MJ, Bradley AJ, Zadoks RN. Invited review: The role of contagious disease in udder health. Journal of Dairy Science. 2009;92:4717-4729\n'},{id:"B13",body:'\nOliver S, Mitchell B. Prevalence of mastitis pathogens in herds participating in a mastitis control program1. Journal of Dairy Science. 1984;67:2436-2440\n'},{id:"B14",body:'\nSmith KL, Todhunter D, Schoenberger P. Environmental mastitis: Cause, prevalence, prevention1, 2. Journal of Dairy Science. 1985;68:1531-1553\n'},{id:"B15",body:'\nBramley AJ. Sources of streptococcus uberis in the dairy herd: I. Isolation from bovine faces and from straw bedding of cattle. Journal of Dairy Research. 1982;49:369-373\n'},{id:"B16",body:'\nZadoks RN, Gillespie BE, Barkema HW, Sampimon OC, Oliver SP, Schukken YH. Clinical, epidemiological and molecular characteristics of Streptococcus uberis infections in dairy herds. Epidemiology and Infection. 2003;130:335-349\n'},{id:"B17",body:'\nAlmeida R, Oliver S. Antiphagocytic effect of the capsule of Streptococcus uberis. Zoonoses and Public Health. 1993;40:707-714\n'},{id:"B18",body:'\nOliver S, Almeida R, Calvinho L. Virulence factors of Streptococcus uberis isolated from cows with mastitis. Zoonoses and Public Health. 1998;45:461-471\n'},{id:"B19",body:'\nMatthews K, Almeida R, Oliver S. Bovine mammary epithelial cell invasion by Streptococcus uberis. Infection and Immunity. 1994;62:5641-5646\n'},{id:"B20",body:'\nAlmeida RA, Kerro Dego O, Headrick SI, Lewis MJ, Oliver SP. Role of Streptococcus uberis adhesion molecule in the pathogenesis of Streptococcus uberis mastitis. Veterinary Microbiology. 2015;179:332-335\n'},{id:"B21",body:'\nAlmeida RA, Fang W, Oliver SP. Adherence and internalization of Streptococcus uberis to bovine mammary epithelial cells are mediated by host cell proteoglycans. FEMS Microbiology Letters. 1999;177:313-317\n'},{id:"B22",body:'\nPatel D, Almeida RA, Dunlap JR, Oliver SP. Bovine lactoferrin serves as a molecular bridge for internalization of Streptococcus uberis into bovine mammary epithelial cells. Veterinary Microbiology. 2009;137:297-301\n'},{id:"B23",body:'\nFang W, Oliver SP. Identification of lactoferrin-binding proteins in bovine mastitis-causing Streptococcus uberis. FEMS Microbiology Letters. 1999;176:91-96\n'},{id:"B24",body:'\nAlmeida RA, Luther DA, Park HM, Oliver SP. Identification, isolation, and partial characterization of a novel Streptococcus uberis adhesion molecule (SUAM). Veterinary Microbiology. 2006;115:183-191\n'},{id:"B25",body:'\nVanderhaeghen W, Piepers S, Leroy F, Van Coillie E, Haesebrouck F, De Vliegher S. Invited review: Effect, persistence, and virulence of coagulase-negative Staphylococcus species associated with ruminant udder health. Journal of Dairy Science. 2014;97:5275-5293\n'},{id:"B26",body:'\nTaponen S, Pyorala S. Coagulase-negative staphylococci as cause of bovine mastitis- not so different from Staphylococcus aureus? Veterinary Microbiology. 2009;134:29-36\n'},{id:"B27",body:'\nNyman AK, Fasth C, Waller KP. Intramammary infections with different non-aureus staphylococci in dairy cows. Journal of Dairy Science. 2018;101:1403-1418\n'},{id:"B28",body:'\nDe Vliegher S, Opsomer G, Vanrolleghem A, Devriese L, Sampimon O, Sol J, et al. In vitro growth inhibition of major mastitis pathogens by Staphylococcus chromogenes originating from teat apices of dairy heifers. Veterinary Microbiology. 2004;101:215-221\n'},{id:"B29",body:'\nGillespie BE, Headrick SI, Boonyayatra S, Oliver SP. Prevalence and persistence of coagulase-negative Staphylococcus species in three dairy research herds. Veterinary Microbiology. 2009;134:65-72\n'},{id:"B30",body:'\nTaponen S, Bjorkroth J, Pyorala S. Coagulase-negative staphylococci isolated from bovine extramammary sites and intramammary infections in a single dairy herd. The Journal of Dairy Research. 2008;75:422-429\n'},{id:"B31",body:'\nFry PR, Middleton JR, Dufour S, Perry J, Scholl D, Dohoo I. Association of coagulase-negative staphylococcal species, mammary quarter milk somatic cell count, and persistence of intramammary infection in dairy cattle. Journal of Dairy Science. 2014;97:4876-4885\n'},{id:"B32",body:'\nWoodward W, Besser T, Ward A, Corbeil L. In vitro growth inhibition of mastitis pathogens by bovine teat skin normal flora. Canadian Journal of Veterinary Research. 1987;51:27\n'},{id:"B33",body:'\nLevison L, Miller-Cushon E, Tucker A, Bergeron R, Leslie K, Barkema H, et al. Incidence rate of pathogen-specific clinical mastitis on conventional and organic Canadian dairy farms. Journal of Dairy Science. 2016;99:1341-1350\n'},{id:"B34",body:'\nPyorala S, Taponen S. Coagulase-negative staphylococci-emerging mastitis pathogens. Veterinary Microbiology. 2009;134:3-8\n'},{id:"B35",body:'\nTaponen S, Koort J, Bjorkroth J, Saloniemi H, Pyorala S. Bovine intramammary infections caused by coagulase-negative staphylococci may persist throughout lactation according to amplified fragment length polymorphism-based analysis. Journal of Dairy Science. 2007;90:3301-3307\n'},{id:"B36",body:'\nTaponen S, Liski E, Heikkila AM, Pyorala S. Factors associated with intramammary infection in dairy cows caused by coagulase-negative staphylococci, Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, Corynebacterium bovis, or Escherichia coli. Journal of Dairy Science. 2017;100:493-503\n'},{id:"B37",body:'\nHogan J, Larry SK. Coliform mastitis. Veterinary Research. 2003;34:507-519\n'},{id:"B38",body:'\nBotrel MA, Haenni M, Morignat E, Sulpice P, Madec JY, Calavas D. Distribution and antimicrobial resistance of clinical and subclinical mastitis pathogens in dairy cows in Rhone-Alpes, France. Foodborne Pathogens and Disease. 2010;7:479-487\n'},{id:"B39",body:'\nBradley AJ, Leach KA, Breen JE, Green LE, Green MJ. Survey of the incidence and aetiology of mastitis on dairy farms in England and Wales. The Veterinary Record. 2007;160:253-257\n'},{id:"B40",body:'\nBurvenich C, Van Merris V, Mehrzad J, Diez-Fraile A, Duchateau L. Severity of E. coli mastitis is mainly determined by cow factors. 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PLoS One. 2015;10:e0134797\n'},{id:"B45",body:'\nPorcherie A, Gilbert FB, Germon P, Cunha P, Trotereau A, Rossignol C, et al. IL-17A is an important effector of the immune response of the mammary gland to Escherichia coli infection. Journal of Immunology. 2016;196:803-812\n'},{id:"B46",body:'\nHerry V, Gitton C, Tabouret G, Reperant M, Forge L, Tasca C, et al. Local immunization impacts the response of dairy cows to Escherichia coli mastitis. Scientific Reports. 2017;7:3441\n'},{id:"B47",body:'\nUSDA APHIS U. Antibiotic Use on U.S. Dairy Operations, 2002 and 2007 (infosheet, 5p, October, 2008) [Online]. 2008a. Available from: https://www.aphis.usda.gov/animal_health/nahms/dairy/downloads/dairy07/Dairy07_is_AntibioticUse_1.pdf [Accessed: 23 March 2020]\n'},{id:"B48",body:'\nUSDA APHIS U. United States Department of Agriculture, Animal Plant Health Inspection Service National Animal Health Monitoring System. Highlights of Dairy 2007 Part III: Reference of dairy cattle health and management practices in the United States, 2007 (info sheet 4p, October, 2008) [Online]. 2008b. Available from: https://www.aphis.usda.gov/animal_health/nahms/dairy/downloads/dairy07/Dairy07_ir_Food_safety.pdf [Accessed: 23 March 2020]\n'},{id:"B49",body:'\nTakahashi T, Satoh I, Kikuchi N. Phylogenetic relationships of 38 taxa of the genus Staphylococcus based on 16S rRNA gene sequence analysis. International Journal of Systematic Bacteriology. 1999;49(Pt 2):725-728\n'},{id:"B50",body:'\nFox LK, Hancock DD. Effect of segregation on prevention of intramammary infections by Staphylococcus aureus. Journal of Dairy Science. 1989;72:540-544\n'},{id:"B51",body:'\nvan Leeuwen WB, Melles DC, Alaidan A, Al-Ahdal M, Boelens HA, Snijders SV, et al. Host-and tissue-specific pathogenic traits of Staphylococcus aureus. Journal of Bacteriology. 2005;187:4584-4591\n'},{id:"B52",body:'\nMcMillan K, Moore SC, McAuley CM, Fegan N, Fox EM. Characterization of Staphylococcus aureus isolates from raw milk sources in Victoria, Australia. BMC Microbiology. 2016;16:169\n'},{id:"B53",body:'\nGraber HU, Naskova J, Studer E, Kaufmann T, Kirchhofer M, Brechbuhl M, et al. Mastitis-related subtypes of bovine Staphylococcus aureus are characterized by different clinical properties. Journal of Dairy Science. 2009;92:1442-1451\n'},{id:"B54",body:'\nCapurro A, Aspan A, Artursson K, Waller KP. Genotypic variation among Staphylococcus aureus isolates from cases of clinical mastitis in Swedish dairy cows. Veterinary Journal. 2010;185:188-192\n'},{id:"B55",body:'\nAnderson KL, Lyman RL. Long-term persistence of specific genetic types of mastitis-causing Staphylococcus aureus on three dairies. 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Microarray based study on virulence-associated genes and resistance determinants of Staphylococcus aureus isolates from cattle. Veterinary Microbiology. 2007;125:128-140\n'},{id:"B60",body:'\nTürkyılmaz S, Tekbıyık S, Oryasin E, Bozdogan B. Molecular epidemiology and antimicrobial resistance mechanisms of methicillin-resistant Staphylococcus aureus isolated from bovine milk. Zoonoses and Public Health. 2010;57:197-203\n'},{id:"B61",body:'\nPantosti A, Sanchini A, Monaco M. Mechanisms of antibiotic resistance in Staphylococcus aureus. Future Microbiology. 2007;2:323-334\n'},{id:"B62",body:'\nUSDA APHIS U. Part III: Health Management and Biosecurity in US Feedlots, 1999. US Department of Agriculture [Online]. 2000. Available from: https://www.aphis.usda.gov/animal_health/nahms/dairy/downloads/dairy07/Dairy07_ir_Food_safety.pdf [Accessed: 23 December 2020]\n'},{id:"B63",body:'\nNeave F, Dodd F, Kingwill R, Westgarth D. Control of mastitis in the dairy herd by hygiene and management. 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Infection and Immunity. 2006;74:3415-3426\n'},{id:"B68",body:'\nden Reijer PM, Sandker M, Snijders SV, Tavakol M, Hendrickx AP, van Wamel WJ. Combining in vitro protein detection and in vivo antibody detection identifies potential vaccine targets against Staphylococcus aureus during osteomyelitis. Medical Microbiology and Immunology. 2017;206:11-22\n'},{id:"B69",body:'\nClarke SR, Foster SJ. Surface adhesins of Staphylococcus aureus. Advances in Microbial Physiology. 2006;51:187-224\n'},{id:"B70",body:'\nHauck CR, Ohlsen K. Sticky connections: Extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Current Opinion in Microbiology. 2006;9:5-11\n'},{id:"B71",body:'\nSpeziale P, Pietrocola G, Rindi S, Provenzano M, Provenza G, Di Poto A, et al. Structural and functional role of Staphylococcus aureus surface components recognizing adhesive matrix molecules of the host. Future Microbiology. 2009;4:1337-1352\n'},{id:"B72",body:'\nBurke FM, McCormack N, Rindi S, Speziale P, Foster TJ. Fibronectin-binding protein B variation in Staphylococcus aureus. BMC Microbiology. 2010;10:160\n'},{id:"B73",body:'\nZecconi A, Scali F. Staphylococcus aureus virulence factors in evasion from innate immune defenses in human and animal diseases. Immunology Letters. 2013;150:12-22\n'},{id:"B74",body:'\nCamussone CM, Calvinho LF. Virulence factors of Staphylococcus aureus associated with intramammary infections in cows: Relevance and role as immunogens. Revista Argentina de Microbiología. 2013;45:119-130\n'},{id:"B75",body:'\nGotz F. Staphylococcus and biofilms. Molecular Microbiology. 2002;43:1367-1378\n'},{id:"B76",body:'\nOtto M. Staphylococcal biofilms. Current Topics in Microbiology and Immunology. 2008;322:207-228\n'},{id:"B77",body:'\nDonlan RM, Costerton JW. Biofilms: Survival mechanisms of clinically relevant microorganisms. 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Injection Practices on U.S. Dairy Operations, 2007 (Veterinary Services Info Sheet 4 p, February 2009) [Online]. 2009. Available from https://www.aphis.usda.gov/animal_health/nahms/dairy/downloads/dairy07/Dairy07_is_InjectionPrac_1.pdf [Accessed: 23 March 2020]\n'},{id:"B138",body:'\nFox LK. Mycoplasma mastitis: Causes, transmission, and control. Veterinary Clinics: Food Animal Practice. 2012;28:225-237\n'},{id:"B139",body:'\nJasper DE. Bovine mycoplasmal mastitis. Advances in Veterinary Science and Comparative Medicine. 1981;25:121-157\n'},{id:"B140",body:'\nDogan B, Klaessig S, Rishniw M, Almeida R, Oliver S, Simpson K, et al. Adherent and invasive Escherichia coli are associated with persistent bovine mastitis. Veterinary Microbiology. 2006;116:270-282\n'},{id:"B141",body:'\nAlmeida RA, Dogan B, Klaessing S, Schukken YH, Oliver SP. Intracellular fate of strains of Escherichia coli isolated from dairy cows with acute or chronic mastitis. Veterinary Research Communications. 2011;35:89-101\n'},{id:"B142",body:'\nBayles KW, Wesson CA, Liou LE, Fox LK, Bohach GA, Trumble W. Intracellular Staphylococcus aureus escapes the endosome and induces apoptosis in epithelial cells. Infection and Immunity. 1998;66:336-342\n'},{id:"B143",body:'\nCraven N, Anderson JC. Phagocytosis of Staphylococcus aureus by bovine mammary gland macrophages and intracellular protection from antibiotic action in vitro and in vivo. The Journal of Dairy Research. 1984;51:513-523\n'},{id:"B144",body:'\nZhao S, Gao Y, Xia X, Che Y, Wang Y, Liu H, et al. TGF-β1 promotes Staphylococcus aureus adhesion to and invasion into bovine mammary fibroblasts via the ERK pathway. Microbial Pathogenesis. 2017;106:25-29\n'},{id:"B145",body:'\nPerez-Casal J, Prysliak T, Kerro Dego O, Potter AA. Immune responses to a Staphylococcus aureus GapC/B chimera and its potential use as a component of a vaccine for S. aureus mastitis. Veterinary Immunology and Immunopathology. 2006;109:85-97\n'},{id:"B146",body:'\nGudding R, McDonald J, Cheville N. Pathogenesis of Staphylococcus aureus mastitis: Bacteriologic, histologic, and ultrastructural pathologic findings. American Journal of Veterinary Research. 1984;45:2525-2531\n'},{id:"B147",body:'\nZecconi A, Cesaris L, Liandris E, Dapra V, Piccinini R. Role of several Staphylococcus aureus virulence factors on the inflammatory response in bovine mammary gland. Microbial Pathogenesis. 2006;40:177-183\n'},{id:"B148",body:'\nHarmon R. Physiology of mastitis and factors affecting somatic cell counts1. Journal of Dairy Science. 1994;77:2103-2112\n'},{id:"B149",body:'\nKeefe G. Update on control of Staphylococcus aureus and Streptococcus agalactiae for management of mastitis. The Veterinary Clinics of North America. Food Animal Practice. 2012;28:203-216\n'},{id:"B150",body:'\nZecconi A. Staphylococcus aureus mastitis: What we need to know to con. Israel Journal of Veterinary Medicine. 2010;65:93-99\n'},{id:"B151",body:'\nMalek dos Reis CB, Barreiro JR, Mestieri L, MADF P, dos Santos MV. Effect of somatic cell count and mastitis pathogens on milk composition in Gyr cows. BMC Veterinary Research. 2013;9:67\n'},{id:"B152",body:'\nAkers RM, Nickerson SC. Mastitis and its impact on structure and function in the ruminant mammary gland. Journal of Mammary Gland Biology and Neoplasia. 2011;16:275-289\n'},{id:"B153",body:'\nSordillo LM, Streicher KL. Mammary gland immunity and mastitis susceptibility. Journal of Mammary Gland Biology and Neoplasia. 2002;7:135-146\n'},{id:"B154",body:'\nHogan J, Smith K. 1987. A practical look at environmental mastitis. The compendium on continuing education for the practicing veterinarian (USA).\n'},{id:"B155",body:'\nGibson H, Sinclair LA, Brizuela CM, Worton HL, Protheroe RG. Effectiveness of selected premilking teat-cleaning regimes in reducing teat microbial load on commercial dairy farms. Letters in Applied Microbiology. 2008;46:295-300\n'},{id:"B156",body:'\nGleeson D, O’Brien B, Flynn J, O’Callaghan E, Galli F. Effect of pre-milking teat preparation procedures on the microbial count on teats prior to cluster application. Irish Veterinary Journal. 2009;62:461-467\n'},{id:"B157",body:'\nDufour S, Frechette A, Barkema HW, Mussell A, Scholl DT. Invited review: Effect of udder health management practices on herd somatic cell count. Journal of Dairy Science. 2011;94:563-579\n'},{id:"B158",body:'\nMordak R, Stewart PA. Periparturient stress and immune suppression as a potential cause of retained placenta in highly productive dairy cows: Examples of prevention. Acta Veterinaria Scandinavica. 2015;57:84\n'},{id:"B159",body:'\nDrackley JK. ADSA foundation scholar award. Biology of dairy cows during the transition period: The final frontier? Journal of Dairy Science. 1999;82:2259-2273\n'},{id:"B160",body:'\nEsposito G, Irons PC, Webb EC, Chapwanya A. Interactions between negative energy balance, metabolic diseases, uterine health and immune response in transition dairy cows. Animal Reproduction Science. 2014;144:60-71\n'},{id:"B161",body:'\nBach A. Associations between several aspects of heifer development and dairy cow survivability to second lactation. Journal of Dairy Science. 2011;94:1052-1057\n'},{id:"B162",body:'\nOliver SP, Jayarao BM, Almeida RA. Foodborne pathogens, mastitis, milk quality, and dairy food safety. In: Proceedings of National Mastitis Council (NMC), 44th meeting, January 16-19. Orlando, FL; 2005. pp. 3-27\n'},{id:"B163",body:'\nScallan E, Hoekstra RM, Angulo FJ, Tauxe RV, Widdowson M-A, Roy SL, et al. Foodborne illness acquired in the United States—Major pathogens. Emerging Infectious Diseases. 2011;17:7-15\n'},{id:"B164",body:'\nJayarao BM, Henning DR. Prevalence of foodborne pathogens in bulk tank milk1. Journal of Dairy Science. 2001;84:2157-2162\n'},{id:"B165",body:'\nGillespie BE, Oliver SP. Simultaneous detection of mastitis pathogens, Staphylococcus aureus, Streptococcus uberis, and Streptococcus agalactiae by multiplex real-time polymerase chain reaction. Journal of Dairy Science. 2005;88:3510-3518\n'},{id:"B166",body:'\nSteele ML, Mcnab WB, Poppe C, Griffiths MW, Chen S, Degrandis SA, et al. Survey of Ontario bulk tank raw Milk for food-borne pathogens. Journal of Food Protection. 1997;60:1341-1346\n'},{id:"B167",body:'\nVan Kessel J, Karns J, Gorski L, McCluskey B, Perdue M. Prevalence of Salmonellae, Listeria monocytogenes, and fecal coliforms in bulk tank milk on US dairies. Journal of Dairy Science. 2004;87:2822-2830\n'},{id:"B168",body:'\nRohrbach BW, Draughon FA, Davidson PM, Oliver SP. Prevalence of Listeria monocytogenes, Campylobacter jejuni, Yersinia enterocolitica, and Salmonella in bulk tank milk: Risk factors and risk of human exposure. Journal of Food Protection. 1992;55:93-97\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Oudessa Kerro Dego",address:"okerrode@utk.edu",affiliation:'
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