Yale School of Public Health Elihu Professor of Biostatistics Jeffrey Townsend has received a 5-year, $4 million grant from the National Institutes of Health as the lead Principal Investigator (PI) on a multi-institutional team studying the role of fungal evolution in spreading disease.
Townsend, and co-PIs Professor Frances Trail of Michigan State University and Associate Professor Anita Sil of the University of California, San Francisco, will use the latest tools in comparative genomics and evolutionary biology to identify key genes underlying fungal spore germination and disease progression. The findings could lead to new diagnostic techniques and potential vaccine candidates for the prevention of endemic fungal diseases.
Approximately 300 fungi are known to cause disease in humans. Some fungal diseases, like Candida auris and Aspergillosis, can be potentially fatal to people with weakened immune systems.
Fungal spores are the microscopic seeds of the fungal world. Scientists know how fungal infections start—when a spore germinates and grows in the environment of its host. But little is known about the genes governing these events. With the NIH funding, Townsend and colleagues will investigate how shifts in gene expression over time allowed different fungi to evolve and gain the ability to attack their hosts in different ways.
"Our approach enables us to use evolutionary history to empower our search for genes whose activity is essential to infection,” said Townsend, who is also a professor of ecology an evolutionary biology and a member of Yale’s Computational Biology and Bioinformatics Program. “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".
Using a powerful tool known as transcriptomics, the team will compare the evolving lineages of seven fungal species whose common ancestor dates back over 300 million years.
“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,” said Trail, a professor specializing in plant fungal pathogens in MSU’s Department of Plant Biology in the College of Natural Science. “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 will direct the comparative evolutionary genomics step of the grant, providing the computational analyses needed to predict the ancestral expression of genes and help identify which genes are essential to the evolution of modes of infection. The Townsend Lab will also perform transcriptomic, gene knockout, and phenotyping research on the model filamentous fungus Neurospora crassa.
Once Townsend identifies gene candidates that have increased in expression, Trail will apply a novel and highly effective method of knocking them out 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 of her expertise in performing similar experiments on highly infectious fungal pathogens of humans. Sil will knock out genes in the most pathogenic fungi in their study—Histoplasma capsulatum and Coccidioides posadasii.