NHMRC Research Fellowship (SRFA): Inflammasome function in protection against infectious disease and autoimmunity (2014–2018)

Abstract:
Inflammasomes are large protein complexes formed in the cytosol which act as platforms for the activation of caspase-1. Caspase-1 mediates the established outcomes of inflammasome activation, which are release of the pro-inflammatory factor interleukin-1beta (IL-1beta), and interleukin-18, as well as an inflammatory lytic form of cell death termed pyroptosis. We have established that the apoptotic caspase, caspase-8, is recruited to the inflammasome and activates apoptosis in parallel to pyroptosis. Inflammasomes depend on oligomerisation of an initiating protein such as AIM2, NLRP3 or NLRC4. This oligomerisation is triggered by a wide array of stimuli such as cytosolic DNA (AIM2), extracellular ATP, bacterial pore forming toxins and crystalline substances including cholesterol (NLRP3) and bacterial flagellin (NLRC4). Inflammasome activation plays a role in numerous human disease states such as gout, atherosclerosis, diabetes, and Alzheimer¿s disease, and therapeutic approaches to damping down inflammasome activity are hotly pursued. Although counterintuitive, we find that the NZB mouse, a model of the human autoimmune disease systemic lupus erythematosus (SLE), has deficiencies in AIM2, NLRC4 and NLRP3 inflammasome function, and is effectively null for NLRP3. This leads to deficient production of IL-1beta in response to mouse cytomegalovirus, Salmonella and Candida, which activate AIM2, NLRC4 and NLRP3 respectively. The NZB mouse may therefore have an abnormal interaction with both pathogens and commensal organisms, which may lead to poor clearance of infection or altered microbiome. I propose that this would lead to ongoing inflammation promoting the development of autoimmunity. The proposed work will (i) continue basic research into the nature of the inflammasome complex and its role in combatting infectious disease and cancer, and (ii) investigate the hypothesis that inflammasome deficiency contributes to autoimmunity.
Grant type:
NHMRC Research Fellowship
Researchers:
  • NHMRC Research Fellow
    School of Chemistry and Molecular Biosciences
    Faculty of Science
    Affiliate Research Fellow
    Institute for Molecular Bioscience
Funded by:
National Health and Medical Research Council