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

  • Aug 9, 2019
  • NIH, fungal diseases, fungal evolution, Faculty, Research
  • Homepage News, Faculty & Staff, Research, College of Natural Science, Plant Biology
Image of Frances Trail in her lab
Frances Trail, MSU professor of plant biology, developed a gene “knockout” method to uncover the evolutionary roots of pathogenic fungi.Courtesy photo.

Michigan State University plant biologist Frances Trail, is a key member of an exceptional 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.

Providing support for health-related research and development, the R01 is the oldest grant mechanism of the NIH. Trail, who is a co-Principal Investigator (PI) on the grant, is teaming up with Jeffrey Townsend, Elihu Professor of Biostatistics at Yale University (lead PI), and Anita Sil, associate professor in the Department of Microbiology and Immunology at the University of California, San Francisco, who is also a co-PI on the project.

Leveraging their combined years of experience in developmental biology, bioinformatics and fungal pathogenesis, Trail, Townsend and Sil are a multifaceted investigative team that will use the NIH funds 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.

“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.

Images of Aspergillus and Fusarium germinating spores
The focus of Trail’s NIH research will be two strains of opportunistic fungi—the long, thin Fusarium oxysporum (right) and the rounder shaped Aspergillus nidulans—both captured in the stage of spore germination. Photo courtesy of Frances Trail

"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.

 

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