The Tenthorey lab studies how the mammalian innate immune system evolves to prevent viral infection. Innate immunity is the body’s first line of defense against infection, and its activation is essential for triggering adaptive immune responses like antibodies. How innate immune proteins recognize invading viruses and act to block their infection cycle is not yet understood at a mechanistic level. We seek to fill that gap by studying innate immunity through multiple lenses: biochemical, biophysical, structural, and evolutionary.

One of the most difficult challenges that the innate immune system faces is an evolutionary problem. Innate immune proteins are “germline-encoded”, meaning that unlike adaptive immunity, they do not generate sequence diversity within an individual host. Nevertheless, their viral targets have massive evolutionary potential and can rapidly evolve to escape innate immune defense. In response, innate immune proteins evolve rapidly (for a mammalian host, at least) to select counter-mutations that regain defense, which viruses evolve to escape again, in an endlessly repeating evolutionary arms race.

How can innate immune proteins possibly compete in these arms races, given that viruses evolve so much faster than their mammalian hosts? What strategies might allow for temporary or even long-term victory? To answer these fundamental questions, we dissect the evolutionary landscapes (the fitness of accessible sequence space around an extant protein) of innate immune proteins and their viral targets to map the possible evolutionary outcomes. We probe the biophysical features that make such landscapes possible, and we use the incredibly rich data to gain mechanistic insight.