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Evolution-inspired dissection of fungal recognition by mammalian immune receptors.

Award Number: DP2AI192430
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Evolution-inspired dissection of fungal recognition by mammalian immune receptors. - PROJECT SUMMARY Mammalian immune systems are one of the front lines of rapid evolution and genetic innovation. While maintaining the orchestration of finely tuned immune responses throughout, they must combat a wide array of invading microbial pathogens that can quickly evolve new strategies to disguise, manipulate, evade, and destroy. The evolutionary back-and-forth that ensues results in diversification of the sequences, structures, and functions of the factors involved. Studies of these evolutionary arms races have been instrumental to our understanding of the molecular basis of interactions between hosts and viral and bacterial pathogens, and reveal the ways they have shaped the evolution of these species and the vulnerabilities that remain. Despite these successes with viruses and bacteria, studies of pathogenic fungi that integrate evolutionary experimental and analytical frameworks have been largely missing. Fungi are an understudied class of microbial pathogens capable of infecting a diverse range of animals, including humans, with truly devastating effects on the health of these species. Despite their impact on human health and mortality, there remain many open questions about the nature and evolution of interactions between these eukaryotic pathogens and the hosts they infect. Here, we bring this missing evolutionary perspective to the study of host-fungal interactions. In previous work, I identified rapid evolution and recurrent sequence diversification of fungi-detecting innate immune receptors in mammals. In Project 1, we use this hallmark of an evolutionary arms race as a launchpad for understanding— at the molecular level—how mammalian innate immune systems recognize fungi. By combining testing of naturally diversified receptor orthologs along with evolution-guided mutational scanning approaches, we will reveal an unprecedented view into the sequence determinants that are most important for tuning the function of these receptors as well as the selective pressures that drive their evolution in mammals. In Project 2, we will turn our attention to the fungi, and ask the questions of what do fungi change and how do fungi change in order to evade detection by mammalian immune systems. We will use a large collection of genetically diverse strains of the fungal pathogen, Cryptococcus neoformans, and establish a molecular barcoding system for high- throughput strain characterization. This will allow us to explore the impacts of sequence variation on recognition of fungal cells by mammalian immune receptors and immune cells. Our approach will inform models of the adaptive evolutionary processes that have shaped these fungal strains into the strains we encounter today while also revealing the genes and genetic variants that play a role in this process. Collectively, these projects will provide a sweeping view of how evolution on both sides of these host-fungal interactions shapes the outcome of infection across species and between individuals and will give us new tools and insight to better combat these infections in the future.


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: 2026 ( Subtotal = $465,000 )
2026	2026	TRUSTEES OF BOSTON COLLEGE	140 COMMONWEALTH AVE	CHESTNUT HILL	MA	02467	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	9/2/2026	NEW	$465,000
														Subtotal = $465,000

Grand Total All Awards = $465,000

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Evolution-inspired dissection of fungal recognition by mammalian immune receptors.

Award Number: DP2AI192430

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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