UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine

Publication Date

2-16-2016

Document Type

Article

Disciplines

Immunity | Immunology of Infectious Disease

Abstract

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-gamma) receptor signaling. Mal-dependent IFN-gamma receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-gamma signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-gamma-related diseases including autoimmunity and cancer.

Rights and Permissions

Citation: Immunity. 2016 Feb 16;44(2):368-79. doi: 10.1016/j.immuni.2016.01.019. Link to article on publisher's site

Open Access funded by Wellcome Trust. Copyright © 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.1016/j.immuni.2016.01.019

Comments

Full author list omitted for brevity. For full list of authors see article.

Related Resources

Link to Article in PubMed

Keywords

Mal; TIRAP; autophagy; interferon gamma; phagolysosome maturation; tuberculosis

Journal/Book/Conference Title

Immunity

PubMed ID

26885859

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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