Researchers uncover how a harmless spore becomes meningitis-causing pathogen

Among fungal pathogens, the meningoencephalitis-causing Cryptococcus neoformans is the most common cause of fatal disease in humans. An estimated 1 million cases of cryptococcal meningitis occur worldwide annually, and C. neoformans is a major cause of illness in people living with HIV/AIDS. It is ubiquitous in the environment, and inhalation of aerosolized spores and/or yeast is the most common route of infection of humans.  

Despite its widespread existence, how C. neoformans grows from dormant spores into disease-causing yeasts is not fully understood. Now, researchers at the University of Wisconsin-Madison have identified 18 proteins involved in the spore’s formation and germination. The study findings, reported August 28, 2015 in PLOS Genetics, hold the promise of preventing disease by blocking the growth of spores in immunocompromised patients.

"When you inhale a spore, if it can't grow, it can't cause disease," says study leader Christina Hull, PhD, associate professor of biomolecular chemistry at the University of Wisconsin School of Medicine and Public Health in Madison, WI. "Spores are dormant; they hang out until they find a place to grow into yeast, and the human lung is a good place. From there, the yeast can travel to the brain."

Once symptoms of cryptococcal meningitis appear, "the patient has billions of Cryptococcus yeasts growing in the brain," Dr. Hull said. "If you could prevent spores from activating, that might be a preventive therapy for immunocompromised patients so even if they inhale a spore, it cannot grow. That could be huge."

With the novel use of nanoscale liquid chromatography and mass spectrometry, the researchers were able to take a new look at the common process of spore germination. The researchers deleted the genes for the 18 identified proteins and studied the resulting mutants. Surprisingly, they found most of the genes were involved in the process that forms a spore in the first place.

Notably, one of the 18 mutant strains (Isp2) displayed a unique, never-before seen phenotype; it showed a delay in spore germination at the step in which vegetative growth is initiated. This strain could be a promising target for the development of inhibitors to prevent fungal growth and spore-mediated disease, the authors concluded.

“If we develop drugs to stop fungi from making the transition from dormant spore to growing yeast, we can prevent disease in vulnerable patients and ultimately save lives,” Dr. Hull said.