Comparative analyses of how SARS-CoV-2 variants of concern affect the host response in cells of the respiratory tract

Hobman, Tom C | $499,130

Alberta University of Alberta 2021 CIHR Operating Grant

The COVID‑19 pandemic has resulted in the biggest global health crisis in over a century causing ~3 million deaths so far. The causative agent of COVID‑19 is a newly emerged coronavirus (SARS-CoV-2) that has continuously evolved into ever more transmissible and pathogenic variants that has exacerbated the spread of the virus across the globe. Due to their high transmissibility and potential resistance to current vaccines, these newly emerging strains of SARS-CoV-2 have been termed ‘variants of concern (VOCs)’. The most prominent among these VOCs are the UK strain (B1.1.7), South African strain (B.1.351) and the Brazilian strain (P.1). The number of active COVID‑19 cases is again increasing in multiple countries due to the emergence of coronavirus VOCs. These variants contain characteristic genetic mutations in multiple viral genes. While much of the focus has been on mutations in the spike protein gene which can alter binding to host cells and potentially evade vaccine-induced antibodies, it is largely unknown how other mutations in VOCs affect replication and pathogenesis of SARSCoV-2. In this proposal, we will used single cell RNA sequencing to study the interaction of SARSCoV-2 variants with the cells from the upper and lower respiratory tract. Using this technology, we will identify the cell types involved in replication of VOCs and determine the critical changes in gene expression of these cells that affect replication of VOCs. In addition, our recent studies have revealed that SARS-CoV-2 targets peroxisomes during infection. These cellular organelles play a vital role in limiting viral replication and controlling inflammation. As such, we will compare how VOCs affect peroxisome functions relative to earlier strains of the virus. As we have shown that some peroxisome agonists can inhibit replication of early strains of SARS-CoV-2, we will explore the possibility of developing peroxisomal agonists as potential therapeutics against VOCs.

With funding from the Government of Canada

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