Mycobacterium tuberculosisInhibits Autocrine Type I IFN Signaling to Increase Intracellular Survival

Abstract

The type I IFNs (IFN-a and-b) 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-a/b-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-b-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.

Human Alveolar and Splenic Macrophage Populations Display a Distinct Transcriptomic Response to Infection With Mycobacterium tuberculosis

“…The role of IFIT family during Mtb infection remains unknown. In contrast to our observation of IFIT1 upregulation in AMs, a recent study showed that the IFIT1 gene was one of the most downregulated genes in murine BMDMs infected with Mtb H37Rv for 4 days (64). Although no anti-mycobacterial effects were attributed to IFIT1, an early anti-or pro-mycobacterial effect depending on Mtb strain or virulence and macrophage species cannot be ruled out.…”

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

“…8A), suggesting that while Lrrk2 KO macrophages can control Mtb replication early after infection, they are more permissive for replication once the bacteria have established a niche. These results are consistent with a recent report demonstrating that defective IFNAR signaling in BMDMs leads to increased Mtb replication (Banks et al, 2019).…”

“…Mtb is a potent activator of cytosolic DNA sensing (Manzanillo et al, 2012;Watson et al, 2012), and type I IFN is an important biomarker of Mtb infection associated with poor outcomes in humans and in mouse models of infection (Berry et al, 2010). New insights into the requirement of IFNAR signaling for nitric oxide production in macrophages ex vivo, suggest critical roles for type I IFN induction in cell-intrinsic control of Mtb replication (Banks et al, 2019). However, the degree to which these macrophage phenotypes translate to mouse models of infection remains poorly understood.…”

Illuminating host-mycobacterial interactions with functional genomic screening to inhibit mycobacterial pathogenesis

“…Furthermore, deletion of nucleotides TCC in human IFNAR1 (human SNP rs72552343) increases resistance to Mtb (Zhang et al, 2018), as does IFNAR1 deletion in mice ( Ifnar1 −/−) (Mayer-Barber et al, 2014). Type I IFN can exert antimicrobial activity in murine macrophages; however, this effect depends on the production of nitric oxide, which is not consistently associated with a reduced mycobacterial burden in human cells (Banks et al, 2019; Thoma-Uszynski et al, 2001). In our study, perturbations of type I IFN signaling improved host cell survival, decreased bacterial load in both M. bovis BCG and Mtb infections, and interfered with the induction of anti-inflammatory cytokines, e.g., IL-10 and IL-1Ra.…”