Abstract
SummaryHumans 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.
Highlights
Genetic variation in proteins involved in innate immunity, Toll-like receptors (TLRs) and their signaling adaptor proteins, has been proposed to account for variation in susceptibility to infectious pathogens
Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor myeloid differentiation primary response gene 88 (MyD88) adaptor-like (Mal) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk
We report that Mal has a TLR-independent role in interferon-gamma (IFN-g) receptor signaling
Summary
Genetic variation in proteins involved in innate immunity, Toll-like receptors (TLRs) and their signaling adaptor proteins, has been proposed to account for variation in susceptibility to infectious pathogens. MyD88 adaptor-like (Mal), encoded by the gene Toll-interleukin 1 receptor (TIR) domaincontaining adaptor protein (TIRAP), was initially described as a signaling adaptor protein leading to nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) activation downstream of TLR4 (Fitzgerald et al, 2001; Horng et al, 2001) and TLR2 (Horng et al, 2002; Yamamoto et al, 2002). S180L has been associated with altered susceptibility to a number of infectious diseases including severe sepsis, severe pneumococcal disease, Haemophilus influenzae, and malaria (Ferwerda et al, 2009; Khor et al, 2007; Ladhani et al, 2010). The mechanism underlying the effect of the S180L SNP has not yet been elucidated
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