It pays for some organisms to be prepared.

Take Candida glabrata, for instance. This opportunistic fungus is a menace to humans, capable of causing life-threatening bloodstream infections in individuals with a compromised immune system, especially the elderly, diabetic patients, and solid organ transplant recipients.

Now, biologists at the University of Iowa have found that C. glabrata, after being exposed to a mild stress, becomes more resistant to hydrogen peroxide, a chemical weapon employed by the human immune system to eliminate infecting microbes. The biologists further learned that this exposure-to-resistance escalation in C. glabrata does not appear in its close relative, the benign Saccharomyces cerevisiae, also known as brewer’s or baker’s yeast.

“Our findings suggest that pathogenic yeasts may be adapted to the host environment by using nutrient cues to prepare themselves for severe immune-associated stresses,” says Bin He, assistant professor in the Department of Biology and the study’s corresponding author. “This result sheds new light on what makes certain yeast species more pathogenic, and may be used to predict other potential, novel pathogens.”

He’s team devised an experiment to tease out the reactionary differences between the two yeast species. First, the researchers exposed one group to a mild stress, which was depriving them of phosphates, a food source, while the other could consume all it wanted. Both groups then were exposed to hydrogen peroxide, a killing agent deployed by the human immune system (although this experiment did not use human immune cells). The C. glabrata cells that had been denied phosphates survived 3 to 10 times more than the control group when exposed to hydrogen peroxide, the researchers found.

In a separate experiment, baker’s yeast cells denied phosphates showed no improvement in survival when exposed to hydrogen peroxide.

Earlier studies have shown that pathogenic yeasts are more resistant to reactive oxygen agents like hydrogen peroxide than their related harmless cousins (like baker’s yeast). The experiments by He’s research team confirmed those results but also revealed an additional layer of resistance stemming from the stress of being denied the phosphates food source.

“Add it all up—the base resistance and what we found to be this additional layer of resistance—and now you're talking upwards of 50- to even 100-fold difference between the resistance of pathogenic yeasts compared to its closest relatives,” He says.

Microbes such as yeasts combat hydrogen peroxide with an enzyme called catalase. That enzyme decomposes hydrogen peroxide into molecular oxygen and water. But that defensive chemistry takes time to realize: Throw in enough hydrogen peroxide, and the microbe simply doesn’t have the time to brew an effective deterrent. 

So, at least in the case of C. glabrata, it uses a previous skirmish, such as the phosphate deprivation scenario, to gird itself for the larger battle.

“The whole idea here is if the cell can preemptively launch—that is, induce the expression of catalysts and other protective genes before hydrogen peroxide even hits—then it’s prepared. This preparation is the key,” says He, who is affiliated with the Interdisciplinary Graduate Program in Genetics.

The findings matter because it appears some disease-causing yeasts always are present in people. One study found C. glabrata (renamed Nakaseomyces glabrata after being found to be more closely related to another yeast species) is present in the gut of up to 30% of patients. Now, the Iowa researchers report this yeast can become more dangerous when it’s been previously stressed.

“Maybe instead of trying to find ways to kill the yeast, we should try to treat them better,” He says. “We should try not to put them into such a harsh environment that they start to do all these nasty things to survive.”

Iowa biologists investigated this thanks to Jinye Liang, a sixth-year graduate student in biology and the study’s first author. Liang had read a study about how the baker’s yeast successfully braced itself for a future stress when being shortchanged with glucose.

“I was thinking, ‘Since phosphate is so crucial, could it also play a role as a signal for an organism to anticipate the future?’ That was how I started this exploratory journey, using S. cerevisiae and C. glabrata as my experimental organisms.”

When Liang conducted the experiments, it was easy to tell the tale: C. glabrata formed a dense, white spot on the lab slides, meaning more of the yeast cells survived and reproduced. The lab slides of S. cerevisiaewere mostly bare.

“I was so excited that I could hardly believe it,” Liang says, “and when I showed the results to Bin, he was excited, too!”

The study, “Divergence of TORC1-mediated stress response leads to novel acquired stress resistance in a pathogenic yeast,” was first published online Oct. 23 in the journal PLoS Pathogens.

Contributing authors, all from Iowa, include Hanxi Tang, Lindsey Snyder, and Christopher Youngstrom.

The National Institutes of Health and a startup fund from the UI funded the research.