| Summary: | It is widely accepted that different strains of <i>Mycobacterium tuberculosis</i> have variable degrees of pathogenicity and induce different immune responses in infected hosts. Similarly, different strains of <i>Mycobacterium bovis</i> have been identified but there is a lack of information regarding the degree of pathogenicity of these strains and their ability to provoke host immune responses. Therefore, in the current study, we used a mouse model to evaluate various factors involved in the severity of disease progression and the induction of immune responses by two strains of <i>M. bovis</i> isolated from cattle. Mice were infected with both strains of <i>M. bovis</i> at different colony-forming unit (CFU) via inhalation. Gross and histological findings revealed more severe lesions in the lung and spleen of mice infected with <i>M. bovis</i> N strain than those infected with <i>M. bovis</i> C68004 strain. In addition, high levels of interferon-γ (IFN-γ), interleukin-17 (IL-17), and IL-22 production were observed in the serum samples of mice infected with <i>M. bovis</i> N strain. Comparative genomic analysis showed the existence of 750 single nucleotide polymorphisms and 145 small insertions/deletions between the two strains. After matching with the Virulence Factors Database, mutations were found in 29 genes, which relate to 17 virulence factors. Moreover, we found an increased number of virulent factors in <i>M. bovis</i> N strain as compared to <i>M. bovis</i> C68004 strain. Taken together, our data reveal that variation in the level of pathogenicity is due to the mutation in the virulence factors of <i>M. bovis</i> N strain. Therefore, a better understanding of the mechanisms of mutation in the virulence factors will ultimately contribute to the development of new strategies for the control of <i>M. bovis</i> infection.
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