One of the first points of contact of pathogenic coronaviruses during infection is the lung alveolar epithelium. 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 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). We have biochemical and imaging evidence that SARS-CoV-2 activates the complement-lectin pathway to promote cell invasion of alveolar epithelial cells and generate proinflammatory complement peptides. However, our understanding of how the virus does this to facilitate infection and how the virus drives initiation and maintenance of an abnormal host inflammatory response is currently incomplete.
This project will use molecular and biochemical techniques together with cell-based models including human iPSC lines 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 have the potential to lead new therapeutic approaches to coronavirus and other emerging pandemic viruses.
Year 1: 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 2: will define novel attachment receptors the virus exploits via lectin-complement pathway proteins at the alveolar epithelium to enhance ACE2-dependent infection using e.g. lentiviral overexpression, transfection based attachment receptor screens and siRNA/CRISPR-Cas9.
Year 3: will use in vitro co-culture with human monocyte, macrophage and iPSC lines 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.