2022 MEDICAL RESEARCH GRANTS

Recent viral epidemics and the current pandemic have exposed the need for effective, targeted, and robust antiviral therapeutics. A team of five investigators at Seattle Children's Hospital (JDA, SM), Institute for Systems Biology (NSB, RLM), and The Hospital for Sick Children (SickKids) in Toronto (MT) proposes a unique strategy for host-based therapeutics that, if successful, will be broadly applicable and could lead to new classes of antiviral agents with high specificities and low toxicity. When viruses infect cells, they hijack and repurpose the host machinery to produce a massive number of new viral particles. This drain on cellular resources exposes vulnerabilities specific to infected cells and is akin to removing one of the legs of a four-legged table. The table can still stand on three legs but will collapse upon the removal of one of its remaining legs. The team hypothesizes that such virus-induced vulnerabilities can be exploited to selectively disable virally infected cells, thereby disrupting the viral life cycle. Their methodology combines state-of-the-art proteomics, targeted CRISPR screens in human cells that overexpress key viral proteins, and novel computational analyses specifically designed to identify host cell vulnerabilities elicited upon influenza, dengue, or SARS-CoV-2 infection. The team's overall goal is to determine if virus-induced vulnerabilities represent an untapped strategy for host-based antivirals.