Mycobacterium tuberculosis Inhibits Autocrine Type I IFN Signaling to Increase Intracellular Survival

The type I IFNs (IFN-alpha and -beta) are important for host defense against viral infections. In contrast, their role in defense against nonviral pathogens is more ambiguous. In this article, we report that IFN-b signaling in murine bone marrow-derived macrophages has a cell-intrinsic protective capacity against Mycobacterium tuberculosis via the increased production of NO. The antimycobacterial effects of type I IFNs were mediated by direct signaling through the IFN-alpha/beta-receptor (IFNAR), as Abmediated blocking of IFNAR1 prevented the production of NO. Furthermore, M. tuberculosis is able to inhibit IFNAR-mediated cell signaling and the subsequent transcription of 309 IFN-beta-stimulated genes in a dose-dependent way. The molecular mechanism of inhibition by M. tuberculosis involves reduced phosphorylation of the IFNAR-associated protein kinases JAK1 and TYK2, leading to reduced phosphorylation of the downstream targets STAT1 and STAT2. Transwell experiments demonstrated that the M. tuberculosis-mediated inhibition of type I IFN signaling was restricted to infected cells. Overall, our study supports the novel concept that M. tuberculosis evolved to inhibit autocrine type I IFN signaling to evade host defense mechanisms.