# Pathogen-driven evolution of innate antiviral defense mechanisms

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $395,000

## Abstract

PROJECT SUMMARY
Infectious diseases are an enormous burden on global health. 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, 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 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. Based on this evolution-guided approach, our
current work focuses on the importance of several incompletely understood post-transcriptional and post-
translational regulatory mechanisms in host antiviral defense. One current area of focus is investigating the
antiviral mechanisms and evolutionary consequences of a dynamically evolving family of genes, known as
IFITs, that distinguish host from viral mRNAs based on mRNA modifications. Another aim is to determine the
immune functions of a poorly characterized but rapidly evolving family of genes known as PARPs that catalyze
the post-translational addition of ADP-ribose to proteins. Using diverse virology models, coupled with genetic
and biochemical approaches, these studies aim to not only determine the consequences of IFIT and PARP
gene evolution on susceptibility to viral infection, but also to reveal the broader mechanistic roles for mRNA
modifications and ADP-ribosylation in host antiviral defense and cellular regulation. Finally, we are developing
genome wide tools to identify other rapidly evolving but understudied regulatory mechanisms that we
hypothesize are additional determinants of human susceptibility to viral infection. The overall mission of our
work is to use this evolution-guided approach to provide unique insights into mechanisms of host defense and
pathogen immune evasion, species-specific barriers to pathogen replicati...

## Key facts

- **NIH application ID:** 10646458
- **Project number:** 5R35GM133633-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Matthew Daugherty
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10646458

## Citation

> US National Institutes of Health, RePORTER application 10646458, Pathogen-driven evolution of innate antiviral defense mechanisms (5R35GM133633-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10646458. Licensed CC0.

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