Researchers from the University of Utah Health have discovered that a fungus that frequently causes fungal meningitis changes dramatically once it enters the body, enabling it to infect the brain. Studies on mice show that a fungus that has spread to the body shrinks and changes in ways that help the infection spread in just a few days. New tactics for thwarting Cryptococcus neoformans infection and averting negative effects on the host may result from the discovery. A rare but fatal swelling of the brain that affects people with compromised immune systems is most often brought on by Cryptococcus neoformans.
“The lungs contain a wide variety of cryptococcus cells with various shapes and colors. I was therefore shocked to see images of the uniformity of brain cells that my graduate student had shown me, “explains Jessica Brown, Ph.D., senior author of the study and an associate professor of pathology at University of Utah Health. It was implied that only this population of cells was making it that far into the body for some very compelling reason. The study’s lead author is Steven Denham, a PhD who was once one of her graduate students. The peer-reviewed journal Cell Host & Microbe just recently made their research available online.
The fungus adapts rapidly to withstand microenvironments in the body
Brown became fascinated by the fungus after discovering that it could survive in a wide variety of environments. In nature, the organism can be found in decaying wood and bird droppings. The fungus can survive in the lungs if it is accidentally inhaled, and after entering the bloodstream, it can move on to the brain and other organs, each of which has a difficult microenvironment.
Previous research by other scientists revealed that the fungus expands to ten times its normal size in order to survive in the lungs, presumably because it is unable to be destroyed by the host immune system due to its size. Fungal cells, however, are much smaller in other areas of the body. Brown questioned whether the extra-small size of the cells could be a benefit in some other way. They may use this trait to colonize various organs, including the brain.
Her team infected mice with Cryptococcus neoformans of various sizes to find out. The smallest cells, as opposed to medium and large cells, preferred to infect the brain, they discovered. Not only were these cells small, but they also differed in other ways. They had distinctive surface characteristics that were just as crucial for gaining access to the brain as those of larger fungal cells. They activated a different set of genes as well.
This data suggested that the tiny fungal cells, or “seed” cells, as Brown called them, were not merely scaled-down versions of larger cells. They are completely different now.
Brown’s team discovered that phosphate, a particular chemical, could cause the shift after looking for potential triggers. The fact that phosphate is released when tissue is harmed by an infection leads Brown to hypothesize that the chemical builds up in the lungs, the first place where fungi settle after entering the body. So, when the fungal cells rearrange themselves into seed cells, the infection can spread further.
From bird guano to the brain
Strangely enough, the fungi’s capacity to successfully attack the brain may have come from a special source: bird guano. Pigeon droppings are a favorable environment for Cryptococcus neoformans because they contain a lot of phosphate, a molecule that stimulates the development of seed cells. Brown’s team discovered that, unlike anything else they had tried, the gooey stuff pushes C. neoformans into that alternate state.
Brown believes that this could show how the fungus’s pathogenicity first developed. According to her, “We believe that selective pressures from environmental niches like pigeon guano are somehow able to confer on Cryptococcus neoformans the ability to infect mammals.”
Whatever the cause, Brown’s team is currently working to use FDA-approved drugs to prevent the fungus’ ability to spread infection. They are trying to find out if there is already a substance that stops Cryptococcus neoformans from making seed cells. If so, it could be used right away to prevent or treat fungal meningitis.
Co-authors from U of U Health include Li Guo, Steven T. Denham, Brianna Brammer, Krystal Y. Chung, Morgan A. Wambaugh, Joseph M. Bednarek, and Christian T. Moreau, in addition to Brown.
According to research funded by the National Institutes of Health, a dissemination-prone morphotype facilitates extrapulmonary organ entry by the fungus Cryptococcus neoformans.
