Professor Ross Mc Manus

The COVID-19 pandemic poses enormous challenges to the health of the Irish population, north and south. Developments in either jurisdiction may affect the other, necessitating disease management on an all-island basis. Susceptibility to SARS-CoV-2 and disease manifestation are affected by both genetic and environmental/demographic factors - the latter including age, gender and metabolic parameters. Host genomics from HLA/MHC alleles to genes with immune function are known to modify host response and clinical course very considerably in many infectious diseases. Thus there is enormous interest internationally in how host genetics affects COVID-19; however there is no data on the host genomics of the Irish population in relation to COVID-19 currently. This is an important and significant deficit which must be rectified to understand the pandemic dynamics in Ireland. The partners in this application, including Genuity Sciences will sequence (at no cost) whole genomes and transcriptomes of 1000 individuals from Ireland. We will also collect information on gene regulatory mechanisms (epigenetics) and the oral-microbiome. Finally we will address knowledge deficits relating to downstream immune function in these patients to generate an all-Ireland repository of genomic, transcriptomic, epigenetic and immune related data which will be an important tool to combat this disease.

SARS-COV2 infection is threatening acute hospital and intensive care unit capacity globally. There is an acute need for a prognostic test which will identify patients at either high or low risk of developing a severe response to COVID-19 infection. Such a test, by identifying whether the immune response is insufficient or excessive, could also help inform therapeutic options during disease progression, We have a long track-record of investigating immune parameters in hospitalised patients with infection and sepsis. We have previously identified a 6 cytokine signature upon admission that discriminates between patients who will experience an uneventful recovery compared to those who develop sepsis. We have also identified IL-7 as an indicator of severe disease in children with viral bronchiolitis and more recently described characteristic immune deficits in severe patients notably dominated by reduced effector T-lymphocyte differentiation. These findings indicate that defects in the immune response in the early stages of disease are strongly correlated with poor outcome. We propose to investigate patients with mild infection, severe infection and controls using a state-of-the art single cell transcriptomic analysis platform. This will allow us to identify a unique Immune response signature from different cells in patients that have mild vs those with a severe response to infection. This signature will be rapidly transformed into a simple flow cytometry or PCR based prognostic assay that can be run in hospital laboratories. This simple assay will identify individuals likely to develop a severe reaction to SARS-COV2 infection requiring ICU admission, but more importantly, will identify infected individuals that can be safely sent home to self- isolate freeing up critical hospital resources, decreasing costs and reducing the risk of viral spread. Importantly, it will also identify immune deficits in patients, informing evidence-based therapeutic options. This project can deliver a prognostic assay within 6 months.