Experimental Evolution Reveals Redox State Modulates Mycobacterial Pathogenicity

Understanding how Mycobacterium tuberculosis has evolved into a professional pathogen is helpful in studying its pathogenesis and for designing vaccines. We investigated how the evolutionary adaptation of M. smegmatis mc(2)51 to an important clinical stressor H(2)O(2) allows bacteria to undergo coordinated genetic mutations, resulting in increased pathogenicity. Whole-genome sequencing identified a mutation site in the fur gene, which caused increased expression of katG. Using a Wayne dormancy model, mc(2)51 showed a growth advantage over its parental strain mc(2)155 in recovering from dormancy under anaerobic conditions. Meanwhile, the high level of KatG in mc(2)51 was accompanied by a low level of ATP, which meant that mc(2)51 is at a low respiratory level. Additionally, the redox-related protein Rv1996 showed different phenotypes in different specific redox states in M. smegmatis mc(2)155 and mc(2)51, M. bovis BCG, and M. tuberculosis mc(2)7000. In conclusion, our study shows that the same gene presents different phenotypes under different physiological conditions. This may partly explain why M. smegmatis and M. tuberculosis have similar virulence factors and signaling transduction systems such as two-component systems and sigma factors, but due to the different redox states in the corresponding bacteria, M. smegmatis is a nonpathogen, while M. tuberculosis is a pathogen. As mc(2)51 overcomes its shortcomings of rapid removal, it can potentially be developed as a vaccine vector.