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Gene Signature IDs Fungal Infection in Mice

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A Duke University research team has pinned down gene expression signatures in mice that coincide with bloodstream infections caused by the fungal pathogen Candida albicans.

By comparing expression profiles in the blood of infected and uninfected mice, the researchers found a sensitive and specific signature in the infected mice that was not present in the healthy mice. After verifying this signature in another group of mice, the team explored the use of expression patterns for distinguishing between mice with Candida infections and bloodstream infections caused by the bacterial species Staphylococcus aureus — and even for tracking the stage of C. albicans infection.

"Our results show that this new gene-signature test works well to find candidemia in mice that had the infection versus mice without infection," co-lead author Aimee Zaas, a genetics, microbiology, and infectious disease researcher affiliated with Duke University School of Medicine and Duke's Institute for Genome Sciences and Policy, said in a statement. "We were very pleased to learn that we could further distinguish the fungal infection from a [Staphylococcus] infection, another bloodstream disease that shares the same set of symptoms."

Although they still need to do follow-up work in humans, those involved say the study, which appeared online yesterday in Science Translational Medicine, could pave the way for expression-based tests for diagnosing and treating Candida infections.

The team is reportedly in the process of collecting human samples with an eye toward developing a comparable gene expression-based blood test for detecting Candida infection in a clinical setting. At the moment, laboratory culture testing is used to distinguish between bacterial and fungal bloodstream infections — a process that can take two to three days and has limited sensitivity.

"This study provides the basis for development of a blood-gene expression test in humans to detect a life-threatening infection earlier than can be done using currently available methods," senior author Geoffrey Ginsburg, director of the Center for Genomic Medicine in Duke University's Institute for Genome Sciences and Policy, said in a statement.

"This work is also part of a portfolio of blood gene-expression-based tests we are developing to detect viral, bacterial and now fungal infections that will lead to more precise diagnosis and more appropriate therapies for infectious disease," Ginsburg added.

Candidemia and invasive candidiasis are bloodstream infections caused by fungi in the Candida genus. They are particularly problematic among immuno-compromised individuals in hospital or other healthcare settings, the researchers explained, and invasive candidiasis can not only prolong hospital visits but also increases mortality risk by more than ten percent.

For the current study, Zaas, Ginsburg, and co-workers focused on C. albicans, the most common cause of candidemia, looking for gene expression patterns associated with this type of infection in mice.

Using Affymetrix murine 430A 2.0 arrays, they compared the gene expression profiles in blood taken from 28 mice infected with C. albicans and a dozen healthy control mice, analyzing the full probe set and 2,093 probes corresponding to immune response genes separately.

Base on their evaluation of 20 sets of co-expressing genes, the team came up with a signature — involving 82 probes representing 67 genes involved in processes such as immune, defense, or stimulus response — that discerned cases from controls with 96 percent sensitivity and 100 percent specificity.

In the experiments that ensued, the researchers not only validated the signature in another 18 infected mice and five control mice, they also narrowed in on genes that are up- and down-regulated at early and late stages of invasive candidiasis infection.

Finally, by comparing expression patterns in 48 C. albicans-infected mice, 17 healthy control mice, and 17 mice infected with the bacterial species S. aureus, the team also illustrated that it's possible to use gene expression profiles to tell Candida infections apart from bloodstream infections caused by S. aureus.

"These findings provide compelling evidence that blood gene expression can accurately discriminate classes of infectious pathogens, specifically fungal infection from a common bacterial bloodstream infection," the researchers wrote, "and may potentially serve as a useful diagnostic for triaging treatment decisions for nosocomial infections, specifically candidemia."

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