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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.

Domestic pigs share many similarities with humans in their pulmonary anatomy, physiology, and immunology. Accordingly, pigs have been shown to be valuable models to study human tuberculosis (TB). Here we examined the outcome of disease in domestic pigs challenged via two different routes with either the human-adapted TB bacillus Mycobacterium tuberculosis or the zoonotic bovine TB bacillus M. bovis in head-to-head comparisons. We found that pigs challenged intravenously with M. bovis AF2122/97 exhibited severe morbidity and rapid onset of mortality, accompanied by higher tissue bacterial burden and necrosis compared to pigs challenged similarly with M. tb Erdman. Concordantly, pigs challenged with aerosolized M. bovis AF2122/97 exhibited reduced weight gain and more severe pathology than pigs challenged similarly with M. tb Erdman. Moreover, pigs aerosol-challenged with M. bovis AF2122/97 exhibited a spectrum of granulomatous lesions ranging from small well-contained granulomas to caseous-necrotic lesions mimicking active TB disease in humans. In contrast, pigs aerosol-challenged with M. tb Erdman exhibited arrested granuloma development. Irrespective of challenge dose and pathological outcome however, peripheral IFN-γ responses were similar in both M. bovis AF2122/97 and M. tb Erdman challenged pigs. This study demonstrates domestic pigs can support infections with M. bovis and M. tb and develop pathology similar to what is observed in humans. And although M. bovis AF2122/97 appears to be more virulent than M. tb Erdman, both strains can be used to model TB in domestic pigs, depending on whether one wishes to recapitulate either acute and active TB or latent TB infections.