Program in Emerging Infectious Diseases (EID)

“Toll-like receptor signaling in innate immunity: just what does MAL do”

By Dr Ashley MansellMonash Institute of Medical ResearchToll‐Like Receptor (TLR) Signalling Laboratory

Abstract:

Initiation of the innate immune response requires agonist recognition by pathogen-recognition receptors such as the Toll-like receptors (TLRs). TIR domain-containing adaptors are critical in orchestrating the signal transduction pathways after TLR activation and are responsible for ‘scultping’ the optimal immune response. MAL/ TIRAP is involved in bridging MyD88 to TLR2 and TLR4 in response to bacterial infection. Our studies have characterised the role of MAL in regulating the activation of innate immunity via NF-B induction of pro-inflammation and the critical role MAL plays in signal transduction.

We have also recently begun investigating the role of the Influenza A virus protein PB1-F2 found in pandemic strains of IAV and its role in inflammation. We show that PB1-F2 from pathogenic IAV induces IL-1 secretion via caspase-1 and the NLRP3 inflammasome in humans and mice. Inflammation induced by PB1-F2 was abrogated in NLRP3 deficient mice. To our knowledge, this is the first characterization of the mechanism of PB1-F2-mediated NLRP3 inflammasome complex activation, providing further understanding of PB1-F2 contribution to the enhanced inflammatory phenotype in pathogenic influenza infections.

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