Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic of COVID-19. Our lack of understanding about the pathogenesis of SARS-CoV-2 in the human airways is an important barrier to developing effective treatment strategies for COVID-19. So far, we know that COVID-19 disease severity increases with age, with very few severe cases among children. In China, the case fatality ratio was 60-year olds, rising to 15% in those >80. This project will focus on two aspects of the host response of infection, studying how the cells that line the airway respond to the virus, and whether the recruited immune cells (focussing on the behaviour of neutrophils that are the first to respond to infection) the help reduce viral load or contribute to airway damage and the build-up of debris in the airways. We will use an experimental SARS-CoV-2 infection model of the airway epithelium from young children, adults and the elderly. Our objectives are to determine: 1) if the primary site of infection - the nasal epithelium - of the elderly exhibit increased viral replication and increased inflammatory response to SARS-CoV-2 infection compared to children.2) the molecular mechanisms that govern age-determinants of COVID-19 disease severity using single-cell genomic analysis of cultured cells and comparing outputs to the same data from age-matched COVID-19 patients using scRNAseq.3) whether the innate immune response to SARS-CoV2 infected airway epithelium exacerbates inflammation and contributes to the severity of illness in the elderly by measuring a) the intensity of immune cell (neutrophil) recruitment to the airway b) epithelial damage and c) neutrophil phenotype and function.It is important that we understand the reasons for these fundamental differences in responses in order to help determine what the most appropriate therapy is for COVID-19 disease in these age groups. There is much debate about the utility of novel and exsiting anti-virals as well as immune modulator therapies including NSAIDs and Tocilizumab. This project will rapidly deliver new understanding about the viral pathogenesis and the cause of these age-related disparties in disease outcomes. Not only will this help support the development of effective therapeutics in the short-term, underlining the relevance of this model for the preclinical evaluation of antiviral candidates, but it may also highlight important risk factors or protective mechanisms that could be used to develop early interventional or prophylaxtic therapies in the long-term.