Mycobacterium tuberculosis induces immune evasion in macrophages through RNA-binding protein tristetraprolin

Abstract Immune evasion of Mycobacterium tuberculosis (Mtb) facilitates intracellular bacterial growth. The mechanisms of immune evasion, however, are still not fully understood. In this study, we reveal that tristetraprolin (TTP), one of the best characterized RNA-binding proteins controlling stability of the target mRNAs, mediates innate immune evasion of mycobacteria. We found that TTP knockout mice displayed reduced bacterial burden in the early stage after Mtb aerosol challenge. Macrophages deficient in TTP also showed an inhibition in mycobacterial growth. Live mycobacteria induced TTP protein expression in macrophages, which was blocked by mTOR inhibitor rapamycin. Rapamycin promoted TTP protein degradation. Proteasome inhibitor MG-132 recovered the shortened TTP protein half-life induced by rapamycin. Ubiquitination mediated TTP protein degradation triggered by rapamycin in infected macrophages. TTP induction suppressed the expression of iNOS/TNF-α/IL-12/IL-23, and weakened the bactericidal effects in infected macrophages, whereas blocking mTOR pathway with rapamycin enhanced the bactericidal effects of infected macrophages through TTP inhibition. Overall, this study reveals a novel role for RNA-binding protein TTP in Mtb immune evasion mechanisms and provides a potential target for host-directed therapy against TB. R21AI171734 & R21AI151936