Bacterial strains from the Mycobacterium tuberculosis complex (MTBC) are functionally diverse and vary in both geographic distribution and potential to cause tuberculosis (TB) disease. Mycobacterium africanum —a lineage of the MTBC—is restricted to West Africa and causes slower progression to active tuberculosis (TB) after initial infection than other MTBC lineages. We hypothesized that this may be partly due to how bacterial strains from these lineages interact with the host immune response. Specifically, we predicted that M. africanum would induce less of the innate cytokine type I interferon because type I interferon has been shown to contribute to TB disease. Our studies focused on (1) whether diverse MTBC strains induce distinct levels of type I interferon in host cells, (2) the mechanism underlying differential type I interferon induction by diverse MTBC strains, and (3) the consequences of the type I interferon response during infection with diverse MTBC strains. We found that M. africanum induced less mitochondrial stress, less release of mitochondrial DNA and less cGAS- and STING-dependent type I interferon in macrophages than other M. tuberculosis strains. Furthermore, we found that M. africanum contained a polymorphism in the Esx-1 gene locus and was unable to secrete the virulence factor EspB through the Esx-1 secretion system, which may contribute to the reduced type I interferon induction by this strain. Finally, we found that type I interferon signaling was pathogenic during chronic M. africanum infection in mice, and thus that the ability to induce pathogenic levels of type I interferon is likely widespread in MTBC strains. Our data suggest that reduced mitochondrial stress and reduced type I interferon induction may contribute to the attenuation of M. africanum. Moreover, our data show that treatments that limit type I interferon induction could be effective in treating diverse mycobacterial infections. Therefore our studies provide insight into a mycobacterial virulence mechanism and highlight the importance of studying diverse clinical isolates of M. tuberculosis.
|Advisor:||Ernst, Joel D.|
|Commitee:||Loke, P'ng, Mathema, Barun, Schwab, Susan R., Torres, Victor J.|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 78/12(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Pathology, Immunology|
|Keywords:||Innate immunity, Mitochondria, Mycobacteria, Mycobacterium africanum, Mycobacterium tuberculosis, Type I interferon|
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