Project ID CM-HD2023_40

ThemeCM-HD

Co Supervisor 1A SIMS, Liver, Renal. Urology, Transplant, Gastro/Gastro Intestinal Surgery Clinical Academic GroupWebsite

Co Supervisor 1B SIMS, Genetics, Rheumatology, Immunology & Infection CAGWebsite

From coronavirus to hyperinflammation: deciphering the role of lectin recognition in complement pathway activation and inflammation

One of the first points of contact of pathogenic coronaviruses during infection is the alveolar epithelium of the lung. A consequence of infection of these cells is a dysregulated inflammatory response typified by hyper-production of inflammatory mediators that leads to an acute respiratory distress syndrome (ARDS) in severe cases of SARS-CoV-2. We believe that this ‘cytokine storm’ is initiated through the SARS-CoV-2 activation of the complement-lectin pathway (a signalling cascade that plays a crucial role in pathogen sensing and clearance and as a major inducer of other mediators of inflammation). However, our understanding of how the virus drives the initiation and maintenance of this abnormal response is currently incomplete.

This project will use molecular and biochemical techniques together with cell-based models and imaging techniques to investigate the mechanisms and molecular interactions that underlie the response of alveolar epithelial cells to SARS-CoV-2. Findings from this project hashave the potential to lead new therapeutic approaches to coronavirus and other emerging pandemic viruses.

Year 1: will establish in vitro models of SARS-COV-2 infection of alveolar epithelial cells using both pseudovirus reporter systems and live wild type virus.

Year 2: will determine the molecular basis for the activation of the lectin complement pathway by SARS-CoV-2 structural proteins using biochemical, molecular, and pharmacological approaches.

Year 3: will use in vitro co-culture with monocyte/ macrophages to determine how complement activation in alveolar epithelial cells leads to the hyperinflammatory response.

This exciting project interfaces host-pathogen biology, complement biology and immunology and will encourage student growth and development in a supportive research environment.

One representative publication from each co-supervisor:

C Farrar, D Tran, K Li, W Wu, Q. Peng, W Schwaeble, W Zhou, S Sacks. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. Journal of Clinical Investigation 2016 2;126(5):1911-25.

Polycarpou A, Howard M, Farrar CA, Greenlaw R, Fanelli G, Wallis R, Klavinskis LS, Sacks S (2020) Rationale for targeting complement in COVID-19. EMBO Mol Med. 2020 Aug 7;12(8):e12642. doi: 10.15252/emmm.202012642