Primary Supervisor: Prof. A. Bowie, Trinity College Dublin, Ireland
Title: Exploring the role of mitochondria and metabolism in human inflammasome activation by RNA viruses.
Collaborators: Prof. J. Hiscott, Institute Pasteur-Rome, Italy; Dr. K. Pardali, AstraZeneca, Gothenburg, Sweden
Early Stage Researcher: TBA (add once Early Stage Researcher list final)
Inflammasomes are multiprotein complexes formed after the sensing of pathogens or cellular insults by members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family, such as NLRP3, and the pyrin and HIN domain (PYHIN) family, such as AIM2. Inflammasomes activate caspase-1 which leads to the maturation and secretion of interleukin 1 beta (IL-1β) and of IL-18, and also to the induction of pyroptosis, a form of cell death. Inflammasomessuch as NLRP3 represent an important, but often poorly understood, component of the human innate immune response to RNA viruses, including respiratory syncytial virus (RSV) and influenza virus (IAV). Almost all of the mechanistic insights into how inflammasomes are activated, cause cytokine release, and regulate cell death have come from studies in mouse cells. For example, we have shown that after NLRP3 inflammasome activation in mouse bone marrow derived macrophages (BMDMs), mitochondrial depolarisation is required to cause maximal pyroptosis, but is not required for IL-1β release. Numerous studies have suggested roles for the mitochondria in inflammasome regulation in mouse cells, while other recent reports suggest that altered metabolism in macrophages is required for optimal inflammasome-dependent IL-1β production. We have developed biochemical tools and used CRISPR/Cas9 technology to study inflammasome activation in human cells. The aim of this project is to determine the role of mitochondrial function and metabolism in inflammasome activation and regulation after IAV and RSV infection of human cells (both monocytes and primary human epithelial cells). The project will also determine whether RNA virus inflammasome activation is altered in epithelial cells from asthma and/or COPD patients. Overall this project will reveal insights into the host-pathogen interface between RNA viruses and human cells, which will increase our understanding of inflammation during viral infections.