Bovine Immune Response to Vaccination and Infection with Leptospira borgpetersenii Serovar Hardjo

ABSTRACT This study examined the humoral and cellular response of cattle vaccinated with two commercial leptospiral vaccines, Leptavoid and Spirovac, and a novel bacterin vaccine using Seppic Montanide oil emulsion adjuvant. Vaccination was followed by experimental challenge. All vaccinated cattle were protected from colonization of the kidney and shedding of Leptospira in urine, as detected by culture and immunofluorescence assay. Agglutinating antibody titers were detected in vaccinated cattle at 4 weeks following vaccination, with small anamnestic response detected following experimental challenge. Only animals vaccinated with the oil emulsion-adjuvanted bacterin produced significant IgG2 titers following vaccination, and nonvaccinated animals produced serum IgA titers after experimental challenge. CD4+ and γδ T cells from vaccinated cattle proliferated when cultured with antigen ex vivo. Cellular responses included a marked proliferation of γδ T cells immediately following experimental challenge in vaccinated cattle and release of gamma interferon (IFN-γ), interleukin 17a (IL-17a), and IL-12p40 from stimulated cells. Proliferative and cytokine responses were found not just in peripheral mononuclear cells but also in lymphocytes isolated from renal lymph nodes at 10 weeks following experimental challenge. Overall, effects of leptospirosis vaccination and infection were subtle, resulting in only modest activation of CD4+ and γδ T cells. The use of Seppic Montanide oil emulsion adjuvants may shorten the initiation of response to vaccination, which could be useful during outbreaks or in areas where leptospirosis is endemic. IMPORTANCE Leptospirosis is an underdiagnosed, underreported zoonotic disease of which domestic livestock can be carriers. As a reservoir host for Leptospira borgpetersenii serovar Hardjo, cattle may present with reproductive issues, including abortion, birth of weak or infected calves, or failure to breed. Despite years of study and the availability of commercial vaccines, detailed analysis of the bovine immune response to vaccination and Leptospira challenge is lacking. This study evaluated immunologic responses to two efficacious commercial vaccines and a novel bacterin vaccine using an adjuvant chosen for enhanced cellular immune responses. Antigen-specific responsive CD4 and γδ T cells were detected following vaccination and were associated with release of inflammatory cytokines IFN-γ and IL-17a after stimulation. CD4 and γδ cells increased in the first week after infection and, combined with serum antibody, may play a role in clearance of bacteria from the blood and resident tissues. Additionally, these antigen-reactive T cells were found in the regional lymph nodes following infection, indicating that memory responses may not be circulating but are still present in regional lymph nodes. The information gained in this study expands knowledge of bovine immune response to leptospirosis vaccines and infection. The use of oil emulsion adjuvants may enhance early immune responses to leptospiral bacterins, which could be useful in outbreaks or situations where leptospirosis is endemic.

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Protective Killed Leptospira borgpetersenii Vaccine Induces Potent Th1 Immunity Comprising Responses by CD4 and γδ T Lymphocytes

Infection and Immunity ◽

10.1128/iai.69.12.7550-7558.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7550-7558 ◽

Cited By ~ 116

Author(s):

Brian M. Naiman ◽

David Alt ◽

Carole A. Bolin ◽

Richard Zuerner ◽

Cynthia L. Baldwin

Keyword(s):

Immune Response ◽

T Cells ◽

Mononuclear Cells ◽

Flow Cytometric Analysis ◽

Γδ T Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Specific Response ◽

Zoonotic Infections ◽

Leptospira Borgpetersenii ◽

Ifn Γ

ABSTRACT Leptospira borgpetersenii serovar hardjo is the most common cause of bovine leptospirosis and also causes zoonotic infections of humans. A protective killed vaccine against serovar hardjo was shown to induce strong antigen-specific proliferative responses by peripheral blood mononuclear cells (PBMC) from vaccinated cattle by 2 months after the first dose of vaccine. This response was absent from nonvaccinated control cattle. The mean response peaked by 2 months after completion of the two-dose vaccination regimen, and substantial proliferation was measured in in vitro cultures throughout the 7 months of the study period. Variations in magnitude of the response occurred among the vaccinated animals, but by 7 months postvaccination there was a substantial antigen-specific response with PBMC from all vaccinated animals. Up to one-third of the PBMC from vaccinated animals produced gamma interferon (IFN-γ) after 7 days in culture with antigen, as ascertained by flow cytometric analysis, and significant levels of IFN-γ were measured in culture supernatants by enzyme-linked immunosorbent assay. Two-color immunofluorescence revealed that one-third of the IFN-γ-producing cells were γδ T cells, with the remaining cells being CD4+ T cells. The significance of this study is the very potent Th1-type immune response induced and sustained following vaccination with a killed bacterial vaccine adjuvanted with aluminum hydroxide and the involvement of γδ T cells in the response. Moreover, induction of this Th1-type cellular immune response is associated with the protection afforded by the bovine leptospiral vaccine against L. borgpeterseniiserovar hardjo.

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Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis

Infection and Immunity ◽

10.1128/iai.00434-16 ◽

2017 ◽

Vol 85 (7) ◽

Cited By ~ 5

Author(s):

Chiara Ripamonti ◽

Lisa R. Bishop ◽

Joseph A. Kovacs

Keyword(s):

T Cells ◽

Fungal Infections ◽

Intracellular Cytokine Staining ◽

Γδ T Cells ◽

Interleukin 17 ◽

Content Type ◽

Immunosuppressed Patients ◽

Ifn Γ ◽

Immunocompetent Mice ◽

Deficient Mice

ABSTRACT Pneumocystis remains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection with Pneumocystis murina. We also examined the clearance of Pneumocystis infection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peak Pneumocystis levels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+ T cells for the former compared to ∼15% for the latter. Both CD4+ T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance of Pneumocystis infection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice cleared Pneumocystis infection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased during Pneumocystis infection in immunocompetent mice, IL-17A is not required for control of Pneumocystis infection.

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Expression of Regulatory T Cells in Jejunum, Colon, and Cervical and Mesenteric Lymph Nodes of Dogs Naturally Infected with Leishmania infantum

Infection and Immunity ◽

10.1128/iai.01862-14 ◽

2014 ◽

Vol 82 (9) ◽

pp. 3704-3712 ◽

Cited By ~ 19

Author(s):

Maria M. Figueiredo ◽

Beatriz Deoti ◽

Izabela F. Amorim ◽

Aldair J. W. Pinto ◽

Andrea Moraes ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Leishmania Infantum ◽

Parasite Load ◽

Mesenteric Lymph Nodes ◽

Content Type ◽

Mesenteric Lymph ◽

Tnf Α ◽

Ifn Γ

ABSTRACTUsing flow cytometry, we evaluated the frequencies of CD4+and CD8+T cells and Foxp3+regulatory T cells (Tregs) in mononuclear cells in the jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected withLeishmania infantumand in uninfected controls. All infected dogs showed chronic lymphadenitis and enteritis. Despite persistent parasite loads, no erosion or ulcers were evident in the epithelial mucosa. The colon harbored more parasites than the jejunum. Frequencies of total CD4+, total Foxp3, and CD4+Foxp3+cells were higher in the jejunum than in the colon. Despite negative enzyme-linked immunosorbent assay (ELISA) serum results for cytokines, levels of interleukin-10 (IL-10), gamma interferon (IFN-γ), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNF-α) were higher in the jejunum than in the colon for infected dogs. However, IL-4 levels were higher in the colon than in the jejunum for infected dogs. There was no observed correlation between clinical signs and histopathological changes or immunological and parasitological findings in the gastrointestinal tract (GIT) of canines with visceral leishmaniasis. However, distinct segments of the GIT presented different immunological and parasitological responses. The jejunum showed a lower parasite load, with increased frequencies and expression of CD4, Foxp3, and CD8 receptors and IL-10, TGF-β, IFN-γ, and TNF-α cytokines. The colon showed a higher parasite load, with increasing expression of IL-4.Leishmania infantuminfection increased expression of CD4, Foxp3, IL-10, TGF-β, IFN-γ, and TNF-α and reduced CD8 and IL-4 expression in both the jejunum and the colon.

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Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽

10.1128/mbio.00191-20 ◽

2020 ◽

Vol 11 (2) ◽

Author(s):

Jennifer D. Helble ◽

Rodrigo J. Gonzalez ◽

Ulrich H. von Andrian ◽

Michael N. Starnbach

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Chlamydia Trachomatis ◽

Genital Tract ◽

Gamma Interferon ◽

Cell Homing ◽

Content Type ◽

T Cell Homing ◽

Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

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Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

Infection and Immunity ◽

10.1128/iai.00148-11 ◽

2011 ◽

Vol 79 (10) ◽

pp. 3940-3946 ◽

Cited By ~ 16

Author(s):

Cuixia Shi ◽

Bikash Sahay ◽

Jennifer Q. Russell ◽

Karen A. Fortner ◽

Nicholas Hardin ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Borrelia Burgdorferi ◽

Adaptive Immune Response ◽

Γδ T Cells ◽

Content Type ◽

Adaptive Immune ◽

Cytokines And Chemokines

ABSTRACTLittle is known regarding the function of γδ T cells, although they accumulate at sites of inflammation in infections and autoimmune disorders. We previously observed that γδ T cellsin vitroare activated byBorrelia burgdorferiin a TLR2-dependent manner. We now observe that the activated γδ T cells can in turn stimulate dendritic cellsin vitroto produce cytokines and chemokines that are important for the adaptive immune response. This suggested thatin vivoγδ T cells may assist in activating the adaptive immune response. We examined this possibilityin vivoand observed that γδ T cells are activated and expand in number duringBorreliainfection, and this was reduced in the absence of TLR2. Furthermore, in the absence of γδ T cells, there was a significantly blunted response of adaptive immunity, as reflected in reduced expansion of T and B cells and reduced serum levels of anti-Borreliaantibodies, cytokines, and chemokines. This paralleled a greaterBorreliaburden in γδ-deficient mice as well as more cardiac inflammation. These findings are consistent with a model of γδ T cells functioning to promote the adaptive immune response during infection.

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No Beneficial Effects Evident for Enterococcus faecium NCIMB 10415 in Weaned Pigs Infected with Salmonella enterica Serovar Typhimurium DT104

Applied and Environmental Microbiology ◽

10.1128/aem.00395-12 ◽

2012 ◽

Vol 78 (14) ◽

pp. 4816-4825 ◽

Cited By ~ 27

Author(s):

Susanne Kreuzer ◽

Pawel Janczyk ◽

Jens Aßmus ◽

Michael F. G. Schmidt ◽

Gudrun A. Brockmann ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Enterococcus Faecium ◽

Salmonella Enterica ◽

Γδ T Cells ◽

Critical Discussion ◽

Feed Additive ◽

Content Type ◽

Beneficial Effects ◽

Serovar Typhimurium

ABSTRACTSalmonella entericaserovar Typhimurium DT 104 is the major pathogen for salmonellosis outbreaks in Europe. We tested if the probiotic bacteriumEnterococcus faeciumNCIMB 10415 can prevent or alleviate salmonellosis. Therefore, piglets of the German Landrace breed that were treated withE. faecium(n= 16) as a feed additive and untreated controls (n= 16) were challenged withS.Typhimurium 10 days after weaning. The presence of salmonellae in feces and selected organs, as well as the immune response, were investigated. Piglets treated withE. faeciumgained less weight than control piglets (P= 0.05). The feeding ofE. faeciumhad no effect on the fecal shedding of salmonellae and resulted in a higher abundance of the pathogen in tonsils of all challenged animals. The specific (anti-SalmonellaIgG) and nonspecific (haptoglobin) humoral immune responses as well as the cellular immune response (T helper cells, cytotoxic T cells, regulatory T cells, γδ T cells, and B cells) in the lymph nodes, Peyer's patches of different segments of the intestine (jejunal and ileocecal), the ileal papilla, and in the blood were affected in the course of time after infection (P< 0.05) but not by theE. faeciumtreatment. These results led to the conclusion thatE. faeciummay not have beneficial effects on the performance of weaned piglets in the case ofS.Typhimurium infection. Therefore, we suggest a critical discussion and reconsideration ofE. faeciumNCIMB 10415 administration as a probiotic for pigs.

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The influence of experimental administration of low zearalenone doses on the expression of Th1 and Th2 cytokines and on selected subpopulations of lymphocytes in intestinal lymph nodes

Polish Journal of Veterinary Sciences ◽

10.1515/pjvs-2015-0064 ◽

2015 ◽

Vol 18 (3) ◽

pp. 489-497 ◽

Cited By ~ 5

Author(s):

K. Obremski ◽

P. Wojtacha ◽

P. Podlasz ◽

M. Żmigrodzka

Keyword(s):

Immune Response ◽

T Cells ◽

Lymph Nodes ◽

Cytokine Secretion ◽

Control Group ◽

M1 Macrophages ◽

Th1 And Th2 Cytokines ◽

Simultaneous Activation ◽

Ifn Γ ◽

Group Flow

Abstract The aim of this study was to characterize the immune response taking place in ileocecal lymph nodes (ICLN) in control (n=15) and zearalenone (ZEN)-treated (n=15) pigs. The experiment was carried out over 42 days; a dose of 0.1 mg kg−1 feed day−1 of ZEN was administered to the animals. The dose used in the experiment was at a level where no adverse effects are observed (NOAEL) in the ovaries, uterus and vagina. ICLN samples for analysis were collected on the 14th, 28th and 42nd day of the experiment. The analysis of cytokine concentration in the tissues showed that pigs treated with ZEN had an increased level of cytokines produced by helper Th1 lymphocytes (IL-2, IL-12 and IFN-γ) on the 28th day of the experiment. The level of cytokines produced by helper Th2 lymphocytes (IL-4 and IL-10) was characterized by a statistically non-significant upward trend, as compared with the control group. Flow cytometry showed a linear decrease in the percentage of CD21+ B, CD2+ T and CD4+CD8- T cells and an increase in the percentage of CD8+CD4- and TCRγδ + T cells in pigs treated with ZEN. Both ZEN and α-ZEL (α-zearalenone) concentrations increased over time in the liver, but only ZEN concentration increased in ICLN. The results obtained demonstrate that a NOAEL concentration of ZEN shifts the immune response in pig ICLN towards Th1/Th17, probably with a simultaneous activation of M1 macrophages. Moreover, we observed an increase in humoral cytokine secretion; this can be explained by a negative feedback loop and a phenotypic switch of macrophages from M1 to M2, as well as a switch of immune response from Th1 to Th2 type. ZEN can therefore influence the process of cytokine secretion and the percentage of lymphocytes in ileocecal lymph nodes.

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Recruitment of Neutrophils Mediated by Vγ2 γδ T Cells Deteriorates Liver Fibrosis Induced by Schistosoma japonicum Infection in C57BL/6 Mice

Infection and Immunity ◽

10.1128/iai.01020-16 ◽

2017 ◽

Vol 85 (8) ◽

Cited By ~ 11

Author(s):

Li Zheng ◽

Yuan Hu ◽

Yanjuan Wang ◽

Xibao Huang ◽

Yuxin Xu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Liver Fibrosis ◽

Schistosoma Japonicum ◽

Γδ T Cells ◽

T Cell Subsets ◽

Interleukin 17 ◽

Content Type ◽

Ifn Γ

ABSTRACT Conventional adaptive T cell responses contribute to the pathogenesis of Schistosoma japonicum infection, leading to liver fibrosis. However, the role of gamma-delta (γδ) T cells in this disease is less clear. γδ T cells are known to secrete interleukin-17 (IL-17) in response to infection, exerting either protective or pathogenic functions. In the present study, mice infected with S. japonicum are used to characterize the role of γδ T cells. Combined with the infection of S. japonicum, an extremely significant increase in the percentage of neutrophils in the CD45+ cells was detected (from approximately 2.45% to 46.10% in blood and from 0.18% to 7.34% in spleen). Further analysis identified two different γδ T cell subsets that have different functions in the formation of granulomas in S. japonicum-infected mice. The Vγ1 T cells secrete gamma interferon (IFN-γ) only, while the Vγ2 T cells secrete both IL-17A and IFN-γ. Both subtypes lose the ability to secrete cytokine during the late stage of infection (12 weeks postinfection). When we depleted the Vγ2 T cells in infected mice, the percentage of neutrophils in blood and spleen decreased significantly, the liver fibrosis in the granulomas was reduced, and the level of IL-17A in the serum decreased (P < 0.05). These results suggest that during S. japonicum infection, Vγ2 T cells can recruit neutrophils and aggravate liver fibrosis by secreting IL-17A. This is the first report that a subset of γδ T cells plays a partial role in the pathological process of schistosome infection.

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Modulation of Immune Responses to Mycobacterium bovis in Cattle Depleted of WC1+ γδ T Cells

Infection and Immunity ◽

10.1128/iai.70.3.1488-1500.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1488-1500 ◽

Cited By ~ 65

Author(s):

Hilary E. Kennedy ◽

Michael D. Welsh ◽

David G. Bryson ◽

Joseph P. Cassidy ◽

Fiona I. Forster ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Mycobacterium Bovis ◽

Bovine Tuberculosis ◽

Γδ T Cells ◽

Interleukin 4 ◽

In Vivo Model ◽

Peripheral Blood Mononuclear ◽

Ifn Γ

ABSTRACT It is accepted that cell-mediated immune responses predominate in mycobacterial infections. Many studies have shown that CD4+ T cells produce Th1 cytokines, such as gamma interferon (IFN-γ), in response to mycobacterial antigens and that the cytolytic activity of CD8+ cells toward infected macrophages is important. However, the extent and manner in which γδ T cells participate in this response remain unclear. In ruminants, γδ T cells comprise a major proportion of the peripheral blood mononuclear cell population. We have previously shown that WC1+ γδ T cells are involved early in Mycobacterium bovis infection of cattle, but their specific functions are not well understood. Here we describe an in vivo model of bovine tuberculosis in which the WC1+ γδ T cells were depleted from the peripheral circulation and respiratory tract, by infusion of WC1+-specific monoclonal antibody, prior to infection. While no effects on disease pathology were observed in this experiment, results indicate that WC1+ γδ T cells, which become significantly activated (CD25+) in the circulation of control calves from 21 days postinfection, may play a role in modulating the developing immune response to M. bovis. WC1+-depleted animals exhibited decreased antigen-specific lymphocyte proliferative response, an increased antigen-specific production of interleukin-4, and a lack of specific immunoglobulin G2 antibody. This suggests that WC1+ γδ TCR+ cells contribute, either directly or indirectly, toward the Th1 bias of the immune response in bovine tuberculosis—a hypothesis supported by the decreased innate production of IFN-γ, which was observed in WC1+-depleted calves.

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Vaccination and Infection of Swine With Salmonella Typhimurium Induces a Systemic and Local Multifunctional CD4+ T-Cell Response

Frontiers in Immunology ◽

10.3389/fimmu.2020.603089 ◽

2021 ◽

Vol 11 ◽

Author(s):

Selma Schmidt ◽

Elena L. Sassu ◽

Eleni Vatzia ◽

Alix Pierron ◽

Julia Lagler ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Lymph Nodes ◽

T Cell Response ◽

Effector Memory ◽

Cell Immune Response ◽

Control Group ◽

Tnf Α ◽

Ifn Γ

The gram-negative facultative intracellular bacteria Salmonella Typhimurium (STM) often leads to subclinical infections in pigs, but can also cause severe enterocolitis in this species. Due to its high zoonotic potential, the pathogen is likewise dangerous for humans. Vaccination with a live attenuated STM strain (Salmoporc) is regarded as an effective method to control STM infections in affected pig herds. However, information on the cellular immune response of swine against STM is still scarce. In this study, we investigated the T-cell immune response in pigs that were vaccinated twice with Salmoporc followed by a challenge infection with a virulent STM strain. Blood- and organ-derived lymphocytes (spleen, tonsils, jejunal and ileocolic lymph nodes, jejunum, ileum) were stimulated in vitro with heat-inactivated STM. Subsequently, CD4+ T cells present in these cell preparations were analyzed for the production of IFN-γ, TNF-α, and IL-17A by flow cytometry and Boolean gating. Highest frequencies of STM-specific cytokine-producing CD4+ T cells were found in lamina propria lymphocytes of jejunum and ileum. Significant differences of the relative abundance of cytokine-producing phenotypes between control group and vaccinated + infected animals were detected in most organs, but dominated in gut and lymph node-residing CD4+ T cells. IL-17A producing CD4+ T cells dominated in gut and gut-draining lymph nodes, whereas IFN-γ/TNF-α co-producing CD4+ T cells were present in all locations. Additionally, the majority of cytokine-producing CD4+ T cells had a CD8α+CD27- phenotype, indicative of a late effector or effector memory stage of differentiation. In summary, we show that Salmonella-specific multifunctional CD4+ T cells exist in vaccinated and infected pigs, dominate in the gut and most likely contribute to protective immunity against STM in the pig.

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