How myeloid cells control level of inflammasome activation and lytic death and can this control be used for a better vaccine design

PROJECT OVERVIEW

Inflammasomes are immune sensors that respond within minutes to the change in tissue and cell homeostasis upon infection or injury1. They trigger local and systemic inflammatory response and also a death of a compromised (damaged or infected) cell. They make an important part of our antimicrobial defences and can also boost the efficacy of vaccines. However, when overactivated, inflammasomes contribute to chronic inflammation in several inherited and acquired inflammatory diseases (e.g. CAPS syndromes, arthritis) or infections (e.g. COVID). So, understanding the molecular mechanisms that ensure timely activation and termination of inflammasome activity is key to our understanding of where they go wrong in disease.

We recently characterised a post-translational break that prevents premature inflammasome activation in response to pathogen or tissue injury signals2. Others have found that excessive cell death downstream of inflammasome activation is responsible for much of the inflammasome-driven pathology in vivo3. Pore forming protein Gasdermin-D is required for inflammasome driven cell death, and we have only limited knowledge about how Gasdermin-D activity is controlled4 , either in macrophages, or many other cells that express this family of proteins . We recently identified several possible gasdermin-D interacting proteins in activated macrophages, as well as several possible chemical inhibitors of the inflammasome pathway (unpublished). In this project we propose to (a) validate novel interactions; (b) understand how they regulate level of inflammasome activity and cell death; and (c) use this knowledge to tune the level of inflammasome activity and associated cell death for better control of pathological inflammation and better vaccine design5. This project will combine biochemistry and imaging with in vitro and in vivo functional studies to track inflammasome activity. Project will benefit from biochemistry and inflammasome expertise of the PI, imaging expertise within Oxford Zeiss Centre of Excellence, and vaccine design expertise of the co-I.

CO-SUPERVISOR

Anita Milicic, Jenner Investigator, Vaccine Formulation and Adjuvants.

KEYWORDS

Inflammasomes, macrophages, vaccines.

TRAINING OPPORTUNITIES

Biochemistry, imaging, in vitro functional assays, in vivo vaccine studies.

KEY PUBLICATIONS

1. Pandey A et al...,Si Ming Man. Cell biology of inflammasome activation (2021) Trends in cell biology DOI:https://doi.org/10.1016/j.tcb.2021.06.010.
2. Fischer, F.A et al...Di Daniel, E., Bezbradica, J.S. TBK1/IKKe act as an OFF switch to limit NLRP3 inflammasome pathway activation (2021) PNAS, doi: 10.1073/pnas.2009309118.
3. Broz P, Pelegrin P and Shao F.The gasdermins, a protein family executing cell death and inflammation (2020) Nature Reviews Immunology 20, 143–157
4. Fischer, F.A, Chen, K.W., Bezbradica, J.S. Posttranslational and therapeutic control of gasdermin-mediated pyroptosis and inflammation (2021) Frontiers in Immunology, DOI.org/10.3389/fimmu.2021.661162
5. S. Reinke, A. Thakur, C. Gartlan , J.S. Bezbradica, A. Milicic. Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants. (2020) Vaccines 8, 554.

KEY THEMES

Inflammasomes, immunology, inflammation, vaccines