scholarly journals Heterogeneity of Pulmonary Granulomas in Cattle Experimentally Infected With Mycobacterium bovis

2021 ◽  
Vol 8 ◽  
Author(s):  
Mitchell V. Palmer ◽  
Tyler C. Thacker ◽  
Carly Kanipe ◽  
Paola M. Boggiatto
Keyword(s):  
Mycobacterium Bovis ◽  
Bovine Tuberculosis ◽  
Lung Lesion ◽  
Bacterial Burden ◽  
Host Pathogen Interactions ◽  
Tnf Α ◽  
Host Pathogen ◽  
Ifn Γ ◽  
Aerosol Infection ◽  
Pulmonary Granulomas

Mycobacterium bovis is the cause of tuberculosis in most animals, most notably cattle. The stereotypical lesion of bovine tuberculosis is the granuloma; a distinct morphological lesion where host and pathogen interact and disease outcome (i.e., dissemination, confinement, or resolution) is determined. Accordingly, it is critical to understand host-pathogen interactions at the granuloma level. Host-pathogen interactions within individual granulomas at different stages of disease have not been examined in cattle. We examined bacterial burden and cytokine expression in individual pulmonary granulomas from steers at 30, 90, 180, and 270 days after experimental aerosol infection with M. bovis. Bacterial burdens within individual granulomas examined 30 days after infection were greater and more heterogenous (variable) than those examined 90 to 270 days after infection. Bacterial burdens did not correlate with expression of IFN-γ, TNF-α, TGF-β, granuloma stage, or lung lesion score, although there was a modest positive correlation with IL-10 expression. Granuloma stage did have modest positive and negative correlations with TNF-α and IL-10, respectively. Heterogeneity and mean expression of IFN-γ, IL-10 and TNF-α did not differ significantly over time, however, expression of TGF-β at 90 days was significantly greater than that seen at 30 days after infection.

scholarly journals Simultaneous Measurement of Antigen-Stimulated Interleukin-1β and Gamma Interferon Production Enhances Test Sensitivity for the Detection of Mycobacterium bovis Infection in Cattle

2010 ◽  
Vol 17 (12) ◽  
pp. 1946-1951 ◽  
Author(s):  
Gareth J. Jones ◽  
Chris Pirson ◽  
R. Glyn Hewinson ◽  
H. Martin Vordermeier
Keyword(s):  
Mycobacterium Bovis ◽  
Gamma Interferon ◽  
Interleukin 1Β ◽  
Induced Responses ◽  
Readout System ◽  
Necrosis Factor Alpha ◽  
Test Sensitivity ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT In order to identify cytokines that may be useful as candidates for inclusion in diagnostic tests for Mycobacterium bovis infection in cattle, we compared the levels of gamma interferon (IFN-γ), interleukin 1β (IL-1β), IL-4, IL-10, IL-12, macrophage inflammatory protein 1β (MIP-1β), and tumor necrosis factor alpha (TNF-α) in whole-blood cultures from tuberculosis (TB) reactor animals or TB-free controls following stimulation with M. bovis-specific antigens (purified protein derivative from M. bovis [PPD-B] or ESAT-6/CFP-10). In addition to IFN-γ responses, the production of IL-1β and TNF-α was also statistically significantly elevated in TB reactor cattle over that in uninfected controls following stimulation with PPD-B or ESAT-6/CFP-10 peptides. Thus, we evaluated whether the use of these two additional readouts could disclose further animals not detected by measuring IFN-γ alone. To this end, receiver operating characteristic (ROC) analyses were performed to define diagnostic cutoffs for positivity for TNF-α and IL-1β. These results revealed that for ESAT-6/CFP-10-induced responses, the use of all three readouts (IFN-γ, TNF-α, and IL-1β) in parallel increased the sensitivity of detection of M. bovis-infected animals by 11% but also resulted in a specificity decrease of 14%. However, applying only IFN-γ and IL-1β in parallel resulted in a 5% increase in sensitivity without the corresponding loss of specificity. The results for PPD-B-induced responses were similar, although the loss of specificity was more pronounced, even when only IFN-γ and IL-1β were used as readout systems. In conclusion, we have demonstrated that the use of an additional readout system, such as IL-1β, can potentially complement IFN-γ by increasing overall test sensitivity for the detection of M. bovis infection in cattle.

scholarly journals Diagnostic Implications of Antigen-Induced Gamma Interferon, Nitric Oxide, and Tumor Necrosis Factor Alpha Production by Peripheral Blood Mononuclear Cells from Mycobacterium bovis-Infected Cattle

2003 ◽  
Vol 10 (5) ◽  
pp. 960-966 ◽  
Author(s):  
W. R. Waters ◽  
M. V. Palmer ◽  
D. L. Whipple ◽  
M. P. Carlson ◽  
B. J. Nonnecke
Keyword(s):  
Bovine Tuberculosis ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Infected Cattle ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Bovine tuberculosis in the United States has proven costly to cattle producers as well as to government regulatory agencies. While in vivo responsiveness to mycobacterial antigens is the current standard for the diagnosis of tuberculosis, in vitro assays are gaining acceptance, especially as ancillary or complementary tests. To evaluate in vitro indices of cellular sensitization, antigen-induced gamma interferon (IFN-γ), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) responses by blood mononuclear cells from Mycobacterium bovis-infected cattle were quantified and compared. Using an aerosol model of infection, two doses of each of two strains of M. bovis (95-1315 and HC-2045T) were used to induce a range of IFN-γ, NO, and TNF-α responses. Infection-specific increases in NO, but not in IFN-γ or TNF-α, were detected in nonstimulated cultures at 48 h, a finding that is indicative of nonspecific activation and spontaneous release of NO. The infective dose of M. bovis organisms also influenced responses. At 34 days postinfection, IFN-γ, NO, and TNF-α responses in antigen-stimulated cells from cattle receiving 105 CFU of M. bovis organisms were greater than responses of cells from cattle infected with 103 CFU of M. bovis organisms. The NO response, but not the IFN-γ and TNF-α responses, was influenced by infective strains of M. bovis. The TNF-α, NO, and IFN-γ responses followed similar kinetics, with strong positive associations among the three readouts. Overall, these findings indicate that NO and TNF-α, like IFN-γ, may prove useful as indices for the diagnosis of bovine tuberculosis.

scholarly journals Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults

2015 ◽  
Vol 22 (7) ◽  
pp. 778-788 ◽  
Author(s):  
Mardi C. Boer ◽  
Corine Prins ◽  
Krista E. van Meijgaarden ◽  
Jaap T. van Dissel ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Regulatory T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Bcg Vaccination ◽  
Cell Responses ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTMycobacterium bovisbacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ+) interleukin 2-positive (IL-2+) tumor necrosis factor α-positive (TNF-α+) polyfunctional CD4+T cells concurrent with CD4+IL-17A+and CD8+IFN-γ+T cells or, in contrast, virtually absent cytokine responses with induction of CD8+regulatory T cells. Significant induction of polyfunctional CD4+IFN-γ+IL-2+TNF-α+T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8+regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4+T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.

scholarly journals Vaccination of Cattle with a CpG Oligodeoxynucleotide-Formulated Mycobacterial Protein Vaccine and Mycobacterium bovis BCG Induces Levels of Protection against Bovine Tuberculosis Superior to Those Induced by Vaccination with BCG Alone

2005 ◽  
Vol 73 (6) ◽  
pp. 3540-3546 ◽  
Author(s):  
D. Neil Wedlock ◽  
Michel Denis ◽  
Margot A. Skinner ◽  
Jessica Koach ◽  
Geoffrey W. de Lisle ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Bovine Tuberculosis ◽  
Protective Efficacy ◽  
Interleukin 2 ◽  
Significant Enhancement ◽  
Protein Vaccine ◽  
Cpg Oligodeoxynucleotide ◽  
Microbiological Parameters ◽  
Ifn Γ ◽  
High Level

ABSTRACT The development of a subunit protein vaccine for bovine tuberculosis which could be used either in combination with Mycobacterium bovis BCG (to improve the efficacy of that vaccine) or alone would offer significant advantages over currently available strategies. A study was conducted with cattle to determine the protective efficacy of a strategy based on concurrent immunization with an M. bovis culture filtrate (CFP) vaccine and BCG compared to vaccination with either vaccine alone. One group of calves (10 animals per group) was vaccinated subcutaneously with CFP formulated with Emulsigen and combined with a CpG oligodeoxynucleotide (ODN). A second group was vaccinated with both the CFP vaccine and BCG injected at adjacent sites (CFP-BCG). One further group was vaccinated subcutaneously with BCG, while another group served as nonvaccinated control animals. Vaccination with CFP-BCG induced levels of antigen-specific gamma interferon (IFN-γ) and interleukin-2 (IL-2) in whole-blood cultures that were higher than those induced by vaccination with BCG alone. The combination of CFP and BCG did not enhance the production of antibodies to M. bovis CFP compared to vaccination with CFP alone. Vaccination with CFP alone led to delayed antigen-specific IFN-γ and IL-2 responses. Vaccination with CFP-BCG induced a high level of protection against an intratracheal challenge with virulent M. bovis, based on a significant enhancement of six pathological and microbiological parameters of protection compared with the nonvaccinated group. In contrast, vaccination with BCG alone induced a significant enhancement of protection in only one parameter, while CFP alone induced no protection. These results suggest that a combination of a CpG ODN-formulated protein vaccine and BCG offers better protection against bovine tuberculosis than does BCG alone.

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

2002 ◽  
Vol 70 (3) ◽  
pp. 1488-1500 ◽  
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.

scholarly journals Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination with Mycobacterium bovis BCG and Infection with Mycobacterium tuberculosis

2009 ◽  
Vol 77 (11) ◽  
pp. 4837-4846 ◽  
Author(s):  
Ajay Grover ◽  
Jennifer Taylor ◽  
JoLynn Troudt ◽  
Andrew Keyser ◽  
Kimberly Arnett ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Mycobacterium Bovis ◽  
T Cell Activation ◽  
Guinea Pigs ◽  
Cell Activation ◽  
Activated T Cells ◽  
Bcg Vaccination ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT The guinea pig model of tuberculosis is used extensively in assessing novel vaccines, since Mycobacterium bovis BCG vaccination effectively prolongs survival after low-dose aerosol infection with virulent M. tuberculosis. To better understand how BCG extends time to death after pulmonary infection with M. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+ CD62Llow and CD8+ CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+ CD62Llow T cells at day 40, although the numbers of CD8+ CD62Llow T cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.

scholarly journals Cellular and Cytokine Responses in the Granulomas of Asymptomatic Cattle naturally infected with Mycobacterium bovis in Ethiopia

2020 ◽  
Author(s):  
Begna Tulu ◽  
Henny M Martineau ◽  
Aboma Zewude ◽  
Fekadu Desta ◽  
David A Jolliffe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Addis Ababa ◽  
Natural Infection ◽  
Stage Iv ◽  
Stage I ◽  
Tnf Α ◽  
Ifn Γ ◽  
Culture Positive ◽  
Culture Negative

ABSTRACTCellular (CD3+ T cell and CD68+ macrophages), cytokines (IFN-γ+ and TNF-α+) and effector molecule (iNOS+) responses were evaluated in the lymph nodes and tissue of cattle naturally infected with Mycobacterium bovis. Detailed post mortem and immunonohistochemical examinations of lesions were performed on 16 cows positive for single intradermal cervical comparative tuberculin test (SICCTT) and identified from dairy farms located around the Addis Ababa City. The severity of the gross lesion was significantly higher (p=0.003) in M. bovis culture positive (n=12) cows than in culture negative (n=4). Immunohistochemical techniques showed that the mean percentage labelling of CD3+ T cells decreased as the stage of granuloma increased from stage I to stage IV in culture positive cows (p<0.001). On the other hand, the proportional fraction of CD68+ macrophages and the concentrations of IFN-γ+, TNF-α+ and iNOS+ increased significantly from stage I to stage IV (p< 0.001) in culture positive cows. At the early stage of the granuloma, the culture negative cows showed significantly higher mean proportions of CD68+ macrophages (p=0.03) as well as the concentrations of iNOS+ (p=0.007) compared to culture positive cows. Similarly, at advanced granuloma stages, culture negative cows demonstrated significantly higher mean proportions of CD3+ T cells (p< 0.001) compared to culture positive cows. Thus, the present study demonstrated that following natural infection of cows with M. bovis, as the stage of granuloma increases from stage I to stage IV, the proportion of CD3+ cells decreases while the immunolabeling fraction of CD68+ macrophages, IFN-γ+, TNF-α and iNOS+ increases.

scholarly journals Effect of Coinfection by fasciola hepatica and mycobacterium bovis on Bovine Tuberculosis Immunodiagnosis in an Enzootic Area Hidalgo State, Mexico.

2018 ◽  
Vol 1 (4) ◽  
pp. 41-54
Author(s):  
García-López Xitli ◽  
Jaramillo-Meza Laura ◽  
Quiroz-Romero Héctor ◽  
Arriaga-Díaz Camila ◽  
Martínez-Maya J. Juan ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Bovine Tuberculosis ◽  
Diagnostic Tests ◽  
Fasciola Hepatica ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ifn Γ ◽  
Group 2 ◽  
Antibody Levels ◽  
Enzootic Area ◽  
Group 1

Parasitic infection by the Fasciola hepatica (F. hepatica) promotes susceptibility towards other infections, such as Mycobacterium bovis. As consequence, could affect diagnostic tests for this disease. Hence, the objective of this study was to assess the impact of F. hepatica coinfection on the most commonly used immunodiagnostic bovine tuberculosis (bTB) tests in field conditions in an enzootic area for both diseases. Thus, from a dairy herd located in Hidalgo State, México, displaying a 59.2% and 28% prevalence of fascioliasis and bTB, respectively. Sixty-one cows were analyzed based on their response towards bTB immunodiagnostic tests, such as Single Intradermal Comparative Tuberculin Test (SICTT), gamma-interferon test (BOVIGAM) and enzyme-linked immunosorbent assay (ELISA), along with the assessment of the F. hepatica parasite load and serodiagnosis by ELISA. Three study groups were formed according to test results. Group 1: coinfected (n=22). Group 2: non-parasitized cows, and positive for bTB tests (n=13) and Group 3: parasitized cows without tuberculosis (n=26). In addition, a group of cows kept in fascioliasis - and tuberculosis-free zones were included (Group 4, n=10). A non-parametric Kruskal-Wallis test and a Dunn test were applied to analyze the results. In Group 1, significant differences were observed regarding IFN-γ production, but not for antibody levels to M. bovis or reactivity towards bovine PPD in relation Group 2. While, Groups 1 and 3 did not display difference in antibody levels against F. hepatica. Differences were observed regarding tuberculosis and Fasciola diagnostic tests when both coinfected and infected groups were compared to controls. It is concluded that F. hepatica coinfection in tuberculous animals studied, depressed the production of IFN-γ towards bovine PPD under in vitro conditions, but its reactivity to the SICTT not show to be altered.

scholarly journals Variation in the Early Host-Pathogen Interaction of Bovine Macrophages with Divergent Mycobacterium bovis Strains in the United Kingdom

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Kirsty Jensen ◽  
Iain J. Gallagher ◽  
Nicholas Johnston ◽  
Michael Welsh ◽  
Robin Skuce ◽  
...  
Keyword(s):  
Cell Death ◽  
United Kingdom ◽  
Mycobacterium Bovis ◽  
Bovine Tuberculosis ◽  
Interferon Response ◽  
Type I ◽  
Content Type ◽  
Host Pathogen Interaction ◽  
The United Kingdom ◽  
Host Pathogen

ABSTRACT Bovine tuberculosis has been an escalating animal health issue in the United Kingdom since the 1980s, even though control policies have been in place for over 60 years. The importance of the genetics of the etiological agent, Mycobacterium bovis , in the reemergence of the disease has been largely overlooked. We compared the interaction between bovine monocyte-derived macrophages (bMDM) and two M. bovis strains, AF2122/97 and G18, representing distinct genotypes currently circulating in the United Kingdom. These M. bovis strains exhibited differences in survival and growth in bMDM. Although uptake was similar, the number of viable intracellular AF2122/97 organisms increased rapidly, while G18 growth was constrained for the first 24 h. AF2122/97 infection induced a greater transcriptional response by bMDM than G18 infection with respect to the number of differentially expressed genes and the fold changes measured. AF2122/97 infection induced more bMDM cell death, with characteristics of necrosis and apoptosis, more inflammasome activation, and a greater type I interferon response than G18. In conclusion, the two investigated M. bovis strains interact in significantly different ways with the host macrophage. In contrast to the relatively silent infection by G18, AF2122/97 induces greater signaling to attract other immune cells and induces host cell death, which may promote secondary infections of naive macrophages. These differences may affect early events in the host-pathogen interaction, including granuloma development, which could in turn alter the progression of the disease. Therefore, the potential involvement of M. bovis genotypes in the reemergence of bovine tuberculosis in the United Kingdom warrants further investigation.

scholarly journals Cellular and Cytokine Responses in the Granulomas of Asymptomatic Cattle Naturally Infected with Mycobacterium bovis in Ethiopia

2020 ◽  
Vol 88 (12) ◽  
Author(s):  
Begna Tulu ◽  
Henny M. Martineau ◽  
Aboma Zewude ◽  
Fekadu Desta ◽  
David A. Jolliffe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Natural Infection ◽  
Stage Iv ◽  
Stage I ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ ◽  
Culture Positive ◽  
Culture Negative

ABSTRACT Cell (CD3+ T cell and CD68+ macrophages), cytokine (interferon gamma-positive [IFN-γ+] and tumor necrosis factor alpha-positive [TNF-α+]), and effector molecule (inducible nitric oxide synthase-positive [iNOS+]) responses were evaluated in the lymph nodes and tissues of cattle naturally infected with Mycobacterium bovis. Detailed postmortem and immunohistochemical examinations of lesions were performed on 16 cows that were positive by the single intradermal cervical comparative tuberculin (SICCT) test and that were identified from dairy farms located around the city of Addis Ababa, Ethiopia. The severity of the gross lesion was significantly higher (P = 0.003) in M. bovis culture-positive cows (n = 12) than in culture-negative cows (n = 4). Immunohistochemical techniques showed that in culture-positive cows, the mean immunolabeling fraction of CD3+ T cells decreased as the stage of granuloma increased from stage I to stage IV (P < 0.001). In contrast, the CD68+ macrophage, IFN-γ+, TNF-α+, and iNOS+ immunolabeling fractions increased from stage I to stage IV (P < 0.001). In the early stages, culture-negative cows showed a significantly higher fraction of CD68+ macrophage (P = 0.03) and iNOS+ (P = 0.007) immunolabeling fractions than culture-positive cows. Similarly, at advanced granuloma stages, culture-negative cows demonstrated significantly higher mean proportions of CD3+ T cells (P < 0.001) than culture-positive cows. Thus, this study demonstrates that, following natural infection of cows with M. bovis, as the stage of granuloma increases from stage I to stage IV, the immunolabeling fraction of CD3+ cells decreases, while the CD68+ macrophage, IFN-γ+, TNF-α+, and iNOS+ immunolabeling fractions increases.

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