Mitochondrial apoptosis and infectious disease responses

Macrophages are innate immune cells that detect environmental, pathogen or host cellular danger molecules, and initiate appropriate immune responses. We previously discovered how pathogens, like Gram-negative bacteria Legionella, inadvertently deplete pro-survival protein MCL-1 in host macrophages, rendering infected cells sensitive to small molecule inhibitors targeting BCL-XL (Speir M et al. Nature Microbiology 2016). We subsequently uncovered that, upon bacterial sensing by Toll-like receptors, specific activation of mitochondrial cell death triggers inflammation via activation of the NOD-like receptor 3 (NLRP3) inflammasome and Interleukin-1beta (Vince JE et al Cell Reports 2018). More recently, we have shown that the related family member A1 acts to delay myeloid cell death, and limit potentially damaging inflammation, during microbial responses (Speir M et al EMBO Reports 2023). This project now aims to further define novel regulators of pathogen-induced mitochondria stress and apoptosis, as well as investigate how these cell death regulatory proteins alter pathogen clearance on a cell-by-cell basis. This project will use our novel gene knockout mice and specific targeted drugs/inhibitors, as well as a range of cell biology and biochemical/molecular approaches (e.g. inflammasome/cell death assays, confocal/time lapse microscopy, ELISA, FACS, Western blotting, Q-PCR, over-expression systems, CRISPR Cas9 gene editing and infectious preclinical disease models).