Evolution-inspired dissection of fungal recognition by mammalian immune receptors

The National Institute of Allergy and Infectious Diseases awarded Boston College $465,000 on September 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research into the evolution-inspired molecular basis of fungal recognition by mammalian immune receptors.

The project applies evolutionary frameworks to understand how mammalian innate immune systems recognize and respond to pathogenic fungi. The research combines testing of naturally diversified immune receptor orthologs with evolution-guided mutational scanning to reveal sequence determinants governing fungal recognition, addressing a gap in the existing literature that has focused extensively on viral and bacterial pathogens but largely overlooked the evolutionary dynamics of host-fungal interactions and their mechanisms.

The award funds research performance in Massachusetts through August 31, 2031. The project is classified as a Project Grant under the Allergy and Infectious Diseases Research program, which supports biomedical research and research training in infectious diseases and related areas at public and private nonprofit institutions.

Abstract

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.