$4 million National Institutes of Health RO1 grant supports "knockout" research on fungal diseases

Michigan State University plant biologist Frances Trail, is part of a team of three scientists to recently receive a 5-year, $4 million National Institutes of Health (NIH) Research Project Grant Program (R01) to study fungal evolution.

Trail, who is a co-principal investigator (PI) on the grant, is teaming up with Jeffrey Townsend of Yale University, lead PI, and Anita Sil of University of California, San Francisco, who is also a co-PI on the project.

Trail, Townsend and Sil aim to identify key genes underlying fungal spore germination and disease progression, leading to diagnostic advancements and potential vaccine candidates for the prevention of endemic fungal diseases.

Trail’s portion amounts to $1.3 million, part of an overall 5-year grant totaling $4 million.

“I was extremely excited to receive the NIH grant,” said Trail, a professor specializing in plant fungal pathogens in the Department of Plant Biology in the MSU College of Natural Science. “This grant will give our ongoing research on the evolution of fungal functional diversity more stability, providing support for an extended research project without the interruption of constantly writing grants.”

Fungal spores are the microscopic seeds of the fungal world. Scientists know they play a key role in fungal infection, but little is known about the genes that govern the germination and the infectious potential of pathogenic spores.

Using a powerful tool known as transcriptomics, the team will compare the evolving lineages of 7 fungal species whose common ancestor dates back over 30 million years. The goal is to identify genes that have evolved a unique function, giving the scientists clues about how the species evolved differences in infection and pathogenesis.

“We examine gene expression in the same stages of spore germination and infection across each of the lineages and ask which of the genes have increased in expression in just one of those lineages,” Trail said. “Our hypothesis is that when expression greatly increases, that gene has taken on a new role, and we think that new role is associated with morphological change, giving it the ability to infect humans and animals.”

Each member of the team has unique skills and technology to carry out their three-step investigation: sifting through millions of years of evolution to find genes that may be responsible for infection, identifying that gene, and manipulating the gene to gain insight into the structural changes it causes in fungal spore germination and infection.

Townsend, an evolutionary biologist and bioinformaticist from Yale’s School of Public Health, will direct the comparative evolutionary genomics step of the grant. His expertise in bioinformatics enables the computational heavy lifting that predicts ancestral expression of genes, providing guidance as to which genes are essential to the evolution of modes of infection.

"Our approach enables us to use evolutionary history to empower our search for genes whose activity is essential to infection,” Townsend said. “It's a great example of how methods developed to perform research in a basic science—evolution—turn out to be extremely important in an applied setting that is important to all of us—medicine."

Once Townsend identifies gene candidates that have increased in expression, Trail proceeds with a novel and highly effective method of knocking them out. Working her way down the list of potential genes provided by Townsend in two species of opportunistic pathogens, Aspergillus nidulans and Fusarium oxysporum, Trail can knock out genes that have changed from their ancestors and examine how the infection process has changed with the loss of that gene’s activity.

“With the ‘knockout’ method, we can begin identifying those genes that are important to infection and may be a new target for drug development,” Trail said. “If we want to eliminate the ability of a pathogen to infect, we need to target the drug to one of the genes that has evolved a function important to infection.”

Sil, a Howard Hughes Medical Institute Early Career Investigator at UC San Francisco, joined the project because neither Trail nor Townsend has the equipment or expertise to work on highly infectious fungal pathogens of humans. Sil will knockout genes in the highly pathogenic fungi in their study—Histoplasma capsulatum and Coccidioides posadasii.

For more information about the NIH’s RO1 grants and their scope, visit: https://grants.nih.gov/grants/funding/r01.htm. 

 

Banner image: Using a powerful tool known as transcriptomics, Trail and the other members of the research team will compare the evolving lineages of seven fungal species whose common ancestor dates back over 30 million years. The goal is to identify genes that have evolved a unique function, giving the scientists clues about how the species evolved differences in infection and pathogenesis. Photo: Anita Sil lab.