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Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations

Award Number: R35GM133633
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations - 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 microbe-driven evolution of cellular functions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $416,811 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	003	7	6/5/2025	NON-COMPETING CONTINUATION	$416,811
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	6	3/24/2025	COMPETING CONTINUATION	$2,385
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	3/24/2025	NON-COMPETING CONTINUATION	-$2,385
														Subtotal = $416,811

Issue Date FY: 2024 ( Subtotal = $416,811 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	7/1/2024	COMPETING CONTINUATION	$416,811
														Subtotal = $416,811

Issue Date FY: 2023 ( Subtotal = $395,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	6/8/2023	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	6/15/2022	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $395,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	6/8/2021	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2020 ( Subtotal = $479,677 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	8/25/2020	SUPPLEMENT FOR EXPANSION	$85,927
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	6/10/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $479,677

Issue Date FY: 2019 ( Subtotal = $393,750 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/23/2019	NEW	$393,750
														Subtotal = $393,750

Grand Total All Awards = $2,892,049

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Evolution of innate antiviral defense mechanisms and other microbe-driven genetic innovations

Award Number: R35GM133633

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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