# Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations > **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $416,811 ## Abstract PROJECT SUMMARY/ABSTRACT Microbes are a constant presence in our environment and impact humanity in diverse ways. In particular, infectious diseases caused by endemic, emerging, and zoonotic pathogens result in millions of human deaths per year. However, we only poorly understand the many mechanisms that hosts have evolved to defend against pathogens and that pathogens have counter-evolved to defeat those defenses. Importantly, the result of these host-pathogen evolutionary conflicts (i.e. whether the host or the pathogen is successful) ultimately determine our susceptibility to infection. It is therefore of paramount importance that we address the following questions: what are the critical genes and mechanisms that protect us from infection from circulating and zoonotic pathogens, how do pathogens counteract those defenses, and how does host genetic variation affect susceptibility to infection? Our research brings an evolution-guided perspective to answering these questions by exploiting natural diversity in host and microbial genomes to identify genetic innovations that have been driven by host-microbe interactions. One motivating insight for this approach is the fact that the interests of pathogens and their hosts are necessarily at odds with one another. That is, if the host successfully defends against a pathogen, there is evolutionary pressure on the pathogen to evolve a way to overcome that defense. Likewise, if the pathogen establishes a successful infection, the host is pressured to adapt. These back-and- forth dynamics drive constant innovation on both sides of host-pathogen molecular interactions, resulting in the wide genetic and functional diversity we see today. Our research explicitly leverages this diversity to discover which host proteins have been driven to rapidly evolve by genetic conflicts with pathogens, in effect allowing pathogens to lead us to the host genes, mechanisms, and pathways that are most important for fitness. Our prior work highlights the utility of this approach by identifying several novel mechanisms in host innate immunity. Based on these evolution-guided insights, our current work focuses on the importance of several incompletely understood post-transcriptional and post-translational regulatory mechanisms in host antiviral defense. At the same time, we will continue to use comparative genomics, virology, and biochemistry to identify other rapidly evolving novel mechanisms in innate immune defenses. Finally, we are using a related evolution-guided approach to discover functional innovations in animals that result not just from adaptation to microbial conflicts, but also from direct co-option of microbial genes by horizontal gene transfer (HGT). The overall mission of our work is to use an evolution-guided multidisciplinary approach to provide unique insights into mechanisms of host defense and pathogen immune evasion, species-specific barriers to pathogen replication and cross-species transmission, and micro... ## Key facts - **NIH application ID:** 10842676 - **Project number:** 2R35GM133633-06 - **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO - **Principal Investigator:** Matthew Daugherty - **Activity code:** R35 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $416,811 - **Award type:** 2 - **Project period:** 2019-08-01 → 2029-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10842676 ## Citation > US National Institutes of Health, RePORTER application 10842676, Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations (2R35GM133633-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842676. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*