Systems Biology Programme Jeannette Tenthorey

10/01/202516:00R_473.10_AULASystems Biology ProgrammeJeannette TenthoreyAssistant Professor - Cellular and Molecular Pharmacology“The Host Strikes Back: Strategies for Evolutionary Warfare”Host: Blanc Medrano, EstherAbstract:The innate immune system is the host’s first, essential line of defense against viruses. It also serves as a critical barrier limiting the spillover of new viruses into humans. Intriguingly, innate immune antiviral proteins are locked in evolutionary arms races with viruses, in which viruses evolve to escape host defenses and antiviral proteins counter-evolve to regain defense. How can the host possibly compete in these evolutionary arms races, given the much faster pace of viral evolution? To answer this question, we take a deep mutational scanning approach to reveal the evolutionary landscapes governing host evolution. Specifically, we find remarkable evolutionary plasticity in TRIM5, an antiviral protein that inhibits HIV and other retroviruses. This tolerance extends to indel mutations, which in turn enable TRIM5 to take “evolutionary leaps” – acquiring new functions that are inaccessible by missense mutations. Our results suggest that antiviral proteins have been selected for mutational resilience to maximize their odds of success in evolutionary arms races, an insight that may explain their success against rapidly evolving viruses.