Aspergillus fumigatus (A. fumigatus) is an important human fungal pathogen, which is responsible for significant morbidity and mortality amongst immunocompromised patients. In recent years, we have made important progress in understanding the molecular mechanisms that regulate sensing of pathogens by pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I like receptors (RLRs). Certain members of the NLR and ALR family assemble a cytoplasmic multi-protein complex termed the 'inflammasome', which activates caspase-1 and induces maturation and secretion of the pro-inflammatory cytokines IL-1? and IL-18. Our recent study demonstrated that intracellular sensing of A. fumigatus requires a coordinated effort between the NLRP3 and AIM2 inflammasomes. However, the molecular mechanisms and signaling pathways leading to activation of these protective responses are completely unknown. In this grant application for renewal, we propose to investigate the signaling pathways regulating activation of inflammasomes driven by A. fumigatus infection. Completion of this proposal is expected to identify the major innate immune sensors that are directly sensing A. fumigatus and unravel the molecular mechanisms that regulate formation of inflammasomes in response to A. fumigatus. These discoveries are expected to identify novel signaling pathways that could be targeted by therapeutic interventions.
NLRs and AIM2 are key intracellular sensors of pathogens which active caspase-1 inflammasome. We have recently identified important roles for these molecules, in providing cytosolic surveillance to fungal infection. However, there is a major gap in the field regarding the signaling pathways and the key molecules essential for the regulation of inflammasome during fungal infections. The proposed studies will contribute to our insight into the key molecular mechanisms by which innate sensors and inflammatory caspases/inflammasomes participate in host defense.
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