Dataset Information

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

ABSTRACT: The type I IFNs (IFN-? and -?) 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-? 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-?/?-receptor (IFNAR), as Ab-mediated 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-?-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.

SUBMITTER: Banks DA

PROVIDER: S-EPMC6456408 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

<i>Mycobacterium tuberculosis</i> Inhibits Autocrine Type I IFN Signaling to Increase Intracellular Survival.

Banks Dallas A DA Ahlbrand Sarah E SE Hughitt V Keith VK Shah Swati S Mayer-Barber Katrin D KD Vogel Stefanie N SN El-Sayed Najib M NM Briken Volker V

Journal of immunology (Baltimore, Md. : 1950) 20190304 8

The type I IFNs (IFN-α and -β) 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-β signaling in murine bone marrow-derived macrophages has a cell-intrinsic protective capacity against <i>Mycobacterium tuberculosis</i> via the increased production of NO. The antimycobacterial effects of type I IFNs were mediated by direct signaling through the IFN-α/β-receptor (IFNAR), as Ab ...[more]

PMID: 30833347

Similar Datasets

Project description:The stable infection of host macrophages by Mycobacterium tuberculosis (Mtb) involves, and depends on, the attenuation of the diverse microbicidal responses mounted by the host cell. This is primarily achieved through targeted perturbations of the host cellular signaling machinery. Therefore, in view of the dependency of the pathogen on host molecules for its intracellular survival, we wanted to test whether targeting such factors could provide an alternate route for the therapeutic management of tuberculosis. To first identify components of the host signaling machinery that regulate intracellular survival of Mtb, we performed an siRNA screen against all known kinases and phosphatases in murine macrophages infected with the virulent strain, H37Rv. Several validated targets could be identified by this method where silencing led either to a significant decrease, or enhancement in the intracellular mycobacterial load. To further resolve the functional relevance of these targets, we also screened against these identified targets in cells infected with different strains of multiple drug-resistant mycobacteria which differed in terms of their intracellular growth properties. The results obtained subsequently allowed us to filter the core set of host regulatory molecules that functioned independently of the phenotypic variations exhibited by the pathogen. Then, using a combination of both in vitro and in vivo experimentation, we could demonstrate that at least some of these host factors provide attractive targets for anti-TB drug development. These results provide a "proof-of-concept" demonstration that targeting host factors subverted by intracellular Mtb provides an attractive and feasible strategy for the development of anti-tuberculosis drugs. Importantly, our findings also emphasize the advantage of such an approach by establishing its equal applicability to infections with Mtb strains exhibiting a range of phenotypic diversifications, including multiple drug-resistance. Thus the host factors identified here may potentially be exploited for the development of anti-tuberculosis drugs.

Dataset Information

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

Publications

<i>Mycobacterium tuberculosis</i> Inhibits Autocrine Type I IFN Signaling to Increase Intracellular Survival.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets