FOR-COVID

Bavarian consortium for research on the pandemic disease COVID-19 (FOR-COVID)

Evolution of virus-host interactions in SARS-CoV-2 VOCs

Projectleader
Prof. Dr. Dr. Andreas Pichlmair

Viruses are obligate intracellular pathogens that exploit the cellular machinery. In a virus-host interaction study, we could establish essential cellular proteins and pathways that SARSCoV- 2 employs or inactivates in order to replicate and spread within a human organism. We could use this information to re-purpose several already existing drugs to show their antiviral properties against SARS-CoV-2. Among the cellular pathways which were of particular importance to limit SARS-CoV-2 spread was the antiviral type-I interferon (IFN) system. In a screening approach conducted in the first funding period, we identified 20 IFN-stimulated genes (ISGs) which affect SARS-CoV-2 growth. In the next funding period, we will focus on two convergent approaches to gain further insights in SARS-CoV-2 vulnerabilities with the aim to identify cellular proteins and pathways that may be manipulated for therapeutic purposes. First, we will establish the interactome of functionally active ISGs which will reveal cellular proteins and pathways that are particularly active against SARS-CoV-2. Secondly, we will study SARS-CoV-2 proteins with mutations occurring in several Variants of Concern (VOCs). Occurrence of such mutations is an indication of their importance for virus-host interactions. We will perform an orthogonal interactome and effectome (the effects of viral protein expression on the cellular proteome) analysis. We will furthermore integrate the cellular response patterns of primary normal human bronchoepithelial cells (NHBEs) to infection with SARS-CoV-2 VOCs. This approach will enable us to generate a proteome-wide perturbation map of SARSCoV- 2 including newly emerging mutations in VOCs. We will tightly collaborate with FOR-COVID partners to merge their large-scale datasets to gain a holistic appreciation on virus susceptibility hubs within this perturbation map. Collectively analysis will provide critical data to evaluate the consequences of newly emerging SARS-CoV-2 mutations and provide new approaches towards rational design of antiviral treatments.

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