Genomic research aids in the effort to drop

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Photo: John Gibbons is Associate Professor of Food Science at UMass Amherst.
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Credit: UMass Amherst

A research team led by a scientist from the University of Massachusetts Amherst has made an important genetic discovery that sheds light on the use of caspofungin to treat a deadly fungal infection. aspergillus smoke, That kills about 100,000 severely immunocompromised people each year.

Normally, healthy people inhale about 50 to 100 germs A. fumigatus Every day when you are outdoors. “Our bodies do an amazing job of recognizing and destroying them,” says a professor of food sciences at UMass Amherst. John Gibbonswhose Microbial Genome Lab Study mushrooms.

But in people with weakened immune systems due to cancer treatment, organ transplants, HIV, COVID-19, and other conditions, A. fumigatus can cause A really bad infection, invasive pulmonary aspergillosis, with a 50 percent mortality rate,” Gibbons says. “And there is a limited way to treat this infection.”

To complicate matters, when given in high concentrations as a treatment for A. fumigatus infection, the antifungal drug sometimes creates a “paradoxical effect of caspofungin” [CPE]Which increases the growth of fungi instead of eliminating them.

In a research published in the magazine spectrum of microbiologyGibbons and senior authors, Xu Zhao, a former graduate student in Gibbons’ lab, and colleagues describe an important first step in the effort to understand when and why treatment with caspofungin could do more harm than good. The team, including scientists from Vanderbilt University, the University of Tennessee Health Science Center and the University of São Paulo in Brazil, completed the first genetic and molecular identification of two genes that contribute to the contrasting effect in A. fumigatus.

“This is one of the first studies to apply genome-wide association analysis (GWA) to identify genes involved in Aspergillus smoke Phenotype,” the paper states.

The team sequenced the genomes of 67 clinical samples, about half of which had CPE, detected genetic differences between groups and then used GWA, a statistical method, to determine how these genetic variants correlate with growth patterns at high concentrations of caspofungin. “We identified a few candidate genes that we thought might contribute to this paradoxical effect,” Gibbons says.

The scientists then used a genetic engineering technology, CRISPR, to delete those candidate genes from the genome, create gene-deletion mutations and enable the researchers to determine that two genes were involved in the paradoxical effect.

“It appears that there are many genes and many genetic variants that contribute to this phenotype,” Gibbons says. “We’re not done yet. One idea is that we could potentially produce new drug targets if we find the full set of genes. We don’t understand the mechanisms yet.”

Ultimately the team hopes that they can use DNA sequencing to understand the genetic basis of different phenotypes in general and to predict clinical benefits if a patient sample A. fumigatus It has a genotype associated with paradoxical effect.

“This is going to be an important tool that can really improve treatment,” Gibbons says.

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