Mycobacterium tuberculosis TlyA Protein Negatively Regulates T Helper (Th) 1 and Th17 Differentiation and Promotes Tuberculosis Pathogenesis.
Bottom Line: Here, we report that TlyA significantly contributes to the pathogenesis of M. tuberculosis.We show that a TlyA mutant M. tuberculosis strain induces increased IL-12 and reduced IL-1β and IL-10 cytokine responses, which sharply contrasts with the immune responses induced by wild type M. tuberculosis.Consequently, animals infected with the TlyA mutant M. tuberculosis organisms exhibited increased host-protective immune responses, reduced bacillary load, and increased survival compared with animals infected with wild type M. tuberculosis.
Affiliation: From the School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, 4001 South Africa.Show MeSH
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Mentions: M. tuberculosis maintains an unhindered lifestyle within susceptible hosts by evading host protective immune responses. In addition to its innate immune evasion mechanisms within macrophages, M. tuberculosis is also successful in modulating adaptive immune responses. Above, we showed that H37RvΔTlyA mutants only exhibited enhanced clearance during the late phase of infection, suggesting that TlyA plays a role in inhibiting adaptive immune responses during disease progression. It is well accepted that Th1 and Th17 cells play a central role in host protection against M. tuberculosis infection. Therefore, we examined the status of adaptive immune components in animals infected by H37RvΔTlyA. As expected, we observed significantly higher T cell proliferative responses upon in vitro challenge with complete soluble M. tuberculosis antigen in mice infected with H37RvΔTlyA, compared with H37Rv (Fig. 2A). This was also reflected by the prevalence of activated CD4+T cells and CD8+T cells in H37RvΔTlyA-infected mice, as deduced by the numbers of CD69-expressing cells. These results suggested that deletion of TlyA in H37Rv promotes activation and proliferation of antigen-specific CD4+T cells in infected animals (Fig. 2, B and C). It is now clear that Th1 and Th17 cells play host-protective roles, whereas Th2 and Treg cells potentiate disease progression. Therefore, we evaluated whether H37RvΔTlyA induced a biased T helper response. Indeed, we found that H37RvΔTlyA-infected animals produced dramatically higher numbers of IFN-γ- and IL-17-producing cells, whereas IL-4-producing cells were significantly reduced as compared with H37Rv-infected mice (Fig. 2, D and E). We also observed that H37RvΔTlyA induced significantly reduced Treg responses compared with H37Rv (Fig. 2, F and G).
Affiliation: From the School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, 4001 South Africa.