Mapping the Emergence and Functional Impact of Novel SARS-CoV-2 Variants

Wrana, Jeffrey L | $446,250

Ontario Sinai Health System 2021 CIHR Operating Grant

Outbreaks of respiratory viral infections over the past 20 years recently culminated in the COVID‑19 pandemic caused by SARS-CoV-2. In a globalized world, repeated cycles of novel viral pathogen is creating an urgent need for population-level molecular screens. SARS-CoV-2 puts this need in sharp relief, as infection leads to generic symptoms of common respiratory pathogens (dry cough, fever and diarrhea), coupled to a broad range of disease manifestations from no/minor symptoms, to acute respiratory distress and death. As the COVID‑19 pandemic expanded across the world, the virus started mutating into variants that possess immune evasive properties. They are often referred to as Variants Of Concern (or VOCs). The emergence of SARS-CoV-2 variants can provide viral reservoirs that can be a source of re-infection and reduced efficacy of vaccines. In this proposal we will use data gathered from systematic screening and sequencing of thousands of positive COVID‑19 samples identified in a Toronto clinical diagnostics lab since December 2020 to identify known and novel VOCs and define the functional impact of the mutations on the ability of the virus to infect/kill cells and be neutralized by antibodies against the virus. It is well established that VOCs are more infectious and more deadly than the WT SARS-CoV-2 strain, but we do not know why. To address this, our team will use next-generation sequencing methods to profile gene-expression in patients infected with wild-type SARS-CoV-2 or VOCs. This will allow us to determine which genes are up/down regulated in response to VOC infection and illuminate potential treatment options. We will use advanced mathematical modelling to monitor and predict the spread and prevalence of the most concerning VOCs. Early identification of viral variants that escape the immune system would provide an opportunity to intervene and prevent spread of therapy-resistant COVID‑19 as well as to instruct public health response.

With funding from the Government of Canada

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