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Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.

Coinfections can alter the adaptive immune responses to bovine tuberculosis (bTB) and hinder accurate diagnosis; however, their effect on host immunity to Mycobacterium bovis and disease progression is not well understood. In this study, we assessed the impact of natural coinfection with bovine leukemia virus (BLV) on immune responses to M. bovis . Among 108 cattle examined, those coinfected with BLV showed a significantly higher intragranulomatous mycobacterial burden and more severe pathological lesions compared to animals infected with M. bovis alone. Additionally, coinfected animals demonstrated a granulomatous response characterized by reduced lymphocyte populations, increased neutrophil infiltration, and diminished granuloma encapsulation, suggesting a compromised antimycobacterial immune response. Supporting this hypothesis, BLV-infected cattle exposed to mycobacterial antigens displayed impaired delayed-type hypersensitivity (type IV hypersensitivity) to a purified protein derivative of M. bovis as well as reduced antibody response. These findings indicate that BLV coinfection influences the immunopathogenesis of bTB, exacerbates disease progression in cattle naturally infected with M. bovis , and may reduce the predictive reliability of diagnostic methods used in bTB control programs.

MicroRNAs contribute to post-transcriptional controls that fine-tune protein expression. Cao and colleagues identify the microRNA miR-29 as a regulator of the expression of interferon-γ protein and show that intracellular infection with pathogens dampens miR-29 expression. Interferon-γ (IFN-γ) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-γ and regulate IFN-γ production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-γ-producing natural killer cells, CD4 + T cells and CD8 + T cells. Moreover, miR-29 suppressed IFN-γ production by directly targeting IFN-γ mRNA. We developed mice with transgenic expression of a 'sponge' target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-γ and lower L. monocytogenes burdens in L. monocytogenes –infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (T H 1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis . Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-γ.

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis . However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis  BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis . Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a ‘One Health’ approach to inform human TB biomarker development and post-exposure vaccine development.

Bovine purified protein derivative (PPD-B), a crude protein extract from Mycobacterium bovis cultures, has been the standard reagent for delayed-type hypersensitivity (DTH) testing in cattle, but its undefined composition and variability compromise reproducibility and specificity. To address these limitations, we developed and evaluated RRbTB-E, a recombinant fusion protein comprising ESAT-6, as a defined alternative for skin testing. RRbTB-E was produced in Escherichia coli, purified by affinity chromatography, and characterized by SDS-PAGE and Western blot. In M. bovis-sensitized guinea pigs, RRbTB-E induced robust DTH reactions comparable to PPD-B, with consistent performance across six independent experiments and long-term stability after storage at 4–8 °C for more than 900 days. Furthermore, RRbTB-E did not induce significant reactions in non-sensitized or Mycobacterium avium–sensitized animals, confirming antigenic specificity. RRbTB-E also elicited DTH responses in Mycobacterium tuberculosis–sensitized guinea pigs. In naturally infected cattle, it triggered responses similar in magnitude to PPD-B, while remaining negative in non-infected animals. These findings support RRbTB-E as a stable, reproducible, and specific candidate for standardized intradermal testing in bovine tuberculosis diagnosis.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine for use against tuberculosis (TB); however, it is known to reduce childhood mortality from infections other than TB. The unspecific protection induced by BCG vaccination has been associated with the induction of memory-like traits of the innate immune system identified as 'trained' immunity. In humans and mouse models, in vitro and in vivo BCG training leads to enhanced production of monocyte-derived proinflammatory cytokines in response to secondary unrelated bacterial and fungal pathogens. While BCG has been studied extensively for its ability to induce innate training in humans and mouse models, BCG's nonspecific protective effects have not been defined in agricultural species. Here, we show that in vitro BCG training induces a functional change in bovine monocytes, characterized by increased transcription of proinflammatory cytokines upon restimulation with the toll-like receptor agonists. Importantly, in vivo, aerosol BCG vaccination in young calves also induced a 'trained' phenotype in circulating peripheral blood mononuclear cells (PBMCs), that lead to a significantly enhanced TLR-induced proinflammatory cytokine response and changes in cellular metabolism compared to PBMCs from unvaccinated control calves. Similar to the long-term training effects of BCG reported in humans, our results suggest that in young calves, the effects of BCG induced innate training can last for at least 3 months in circulating immune populations. Interestingly, however, aerosol BCG vaccination did not 'train' the innate immune response at the mucosal level, as alveolar macrophages from aerosol BCG vaccinated calves did not mount an enhanced inflammatory response to secondary stimulation, compared to cells isolated from control calves. Together, our results suggest that, like mice and humans, the innate immune system of calves can be 'trained'; and that BCG vaccination could be used as an immunomodulatory strategy to reduce disease burden in juvenile food animals before the adaptive immune system has fully matured.

Bovine tuberculosis (bTB) is a threat to cattle health and public safety. The current control programs are hampered by wildlife reservoirs and socioeconomic barriers. Vaccinating cattle with Bacillus Calmette-Guérin (BCG) effectively reduces transmission, offering a potential solution for controlling bTB. A key requirement for vaccination strategies using BCG is the validation of defined antigens to differentiate infections among vaccinated animals (DIVA). We compared tuberculin with DIVA peptide cocktails (ESAT-6, CFP-10, and Rv3615c) in 67 unvaccinated and 67 BCG-vaccinated cattle exposed to M. bovis in a natural setting. The cattle were tested every 4 months with a skin test and every 2 months with interferon-gamma (IFN-γ) release assays (IGRA) over a year of exposure. Before exposure, the DIVA skin, DIVA IGRA, and tuberculin tests showed 100% specificity in unvaccinated control calves. After exposure, the DIVA skin, DIVA IGRA, and comparative cervical tuberculin (CCT) tests had comparable sensitivities of 46% (95% CI 36, 56), 45% (95% CI 35, 55), and 47 (95% CI 37, 57), respectively, when assessed against animals positive by M. bovis culture PCR. The results suggest that test-and-slaughter control strategies using tests with low sensitivity are not expected to be effective in controlling bTB in high-prevalence herds, and highlight an urgent need to improve the sensitivity of diagnostic tests for bTB in these settings.

Bovine tuberculosis (BTB) is an infectious disease of livestock and wildlife species that is caused by pathogenic members of the Mycobacterium tuberculosis complex such as Mycobacterium bovis . Due to the introduction of M. bovis -infected bison in the 1920s, BTB is now endemic in wood bison ( Bison bison athabascae ) population within the Wood Buffalo National Park (WBNP) in northern Canada. This disease poses a grave threat to the long-term survival of this ecologically and culturally important species and has the potential to cause zoonotic TB and spill over to BTB-free livestock and other bison herds that live in the surrounding areas. Thus, effective BTB control strategies in WBNP bison are urgently needed. To this end, we aerosol challenged young bison with different doses of virulent M. bovis and observed disease-associated delayed-type hypersensitivity, gross lung and lymph node pathology and histopathology, as well as M. bovis burden in target organs, thus confirming the establishment of BTB in challenged animals. We then assessed the safety and efficacy of oral live BCG versus oral heat-inactivated M. bovis (HIMB) given in a homologous prime-boost regimen in bison. While both BCG and HIMB offered protection against BTB, BCG-treated bison thrived more, presented with fewer lung lesions at necropsy and lower burden of virulent M. bovis than HIMB-treated animals. Strikingly, oral HIMB induced almost no delayed-type hypersensitivity to intradermal tuberculin while oral live BCG induced very low sensitivity to tuberculin in bison, indicating their potential as DIVA (differentiating infected from vaccinated animals) vaccines for use in this important wildlife species.

Tuberculosis (TB) disease still kills 1-person every 21-seconds. Few TB diagnostic tests are considered truly appropriate for point of care settings. The WHO-endorsed immunodiagnostic Alere Determine Lipoarabinomannan Ag-test (LAM-test) detects Mycobacterium tuberculosis complex LAM in urine, and its use is recommended for TB diagnosis among HIV co-infected individuals with low CD4 T-cell counts. Here we found that a simple 15-minute enzymatic treatment at room temperature of LAM-spiked urine with α-mannosidase (for human TB), and LAM-spiked milk with combined lactase and caseinase (for bovine TB), enhanced 10-fold the detection levels of the LAM-test and thus, improved the detection of LAM by the LAM-test in urine and milk that otherwise could be missed in the field. Future separate clinical research studies specifically designed to address the potential of these findings are required.