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Updated: Mar 25, 2026

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling
Clíona Ní Cheallaigh1, Frederick J Sheedy2, James Harris3
1Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, D08 W9RT, Dublin, Ireland; Adjuvant Research Group, School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 PN40, Dublin, Ireland.
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-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ 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-γ-related diseases including autoimmunity and cancer.
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