This fungus shrinks in size to better infect the brain

A fungus that is a common cause of fungal meningitis undergoes a remarkable transformation once it enters the body, allowing it to infect the brain, according to new research by researchers at the University of Utah Health. Studies in mice show that as the uninvited fungus travels through the body, it shrinks and acquires properties that help infection spread, all within days.

The discovery could lead to new strategies to block Cryptococcus neoformans infection and prevent harmful effects on the host. C. neoformans is the leading cause of a rare but fatal swelling of the brain that occurs in people with weakened immune systems.

“Cryptococcus cells in the lungs are very different with different sizes and different appearance. So when my graduate student showed me pictures of the uniformity of cells from the brain, I was shocked,” says Jessica Brown, Ph.D., associate professor of pathology at U of U Health and the study’s senior author. “That suggested there was a very strong reason why only this population of cells made it this far into the body.” Her former graduate student, Steven Denham, PhD, is lead author on the study. Their research was recently published online in the peer-reviewed journal Cell Host & Microbe.

The fungus quickly adapts to withstand microenvironments in the body

Brown’s fascination with the fungus came from the observation that it thrives in so many different habitats. In the wild, the organism lives in rotting wood and bird droppings. If accidentally inhaled, the fungus can survive in the lungs and then travel in the bloodstream to the brain and other organs, each with its own challenging microenvironment.

Previously, other researchers have found that the fungus can manage to live in the lungs by growing to 10 times its normal size, presumably becoming too large for the host’s immune system to destroy. But in other parts of the body, fungal cells are much smaller. Brown wondered, could the extra small size of the cells be another type of advantage? Perhaps that trait helps them colonize other organs, such as the brain.

To find out, her team infected mice with different sizes of C. neoformans. They found that compared to medium and large cells, the smallest cells preferentially infected the brain. These cells were not only diminutive, but differed in other ways. Compared to larger fungal cells, they had unique properties on their surface that were similarly important for gaining access to the brain. They also turned on another set of genes.

This evidence suggested that the tiny fungal cells, which Brown called “seed” cells, were not just miniature versions of larger cells. They had undergone a wholesale change.

After searching for triggers, Brown’s group found that a specific chemical—phosphate—could induce the switch. Knowing that phosphate is released when tissue is damaged during infection, Brown speculates that the chemical accumulates in the lungs, the first place fungi settle after entering the body. This allows the fungal cells to reconfigure themselves as seed cells, allowing the infection to spread further.

From bird guano to the brain

Curiously, the mushroom’s ability to effectively target the brain may come from a unique source: bird guano. C. neoformans thrives in pigeon droppings, which have high levels of the seed cell-triggering molecule, phosphate. Brown’s team found that the sticky stuff pushes C. neoformans into the alternate state like nothing else they had tried.

Brown believes this could demonstrate how the fungus’ pathogenicity arose in the first place. “We think that selective pressure from environmental niches like pigeon guano is somehow able to give C. neoformans the ability to infect mammals,” she says.

Regardless of how the fungi’s infectious property arose, Brown’s team is now trying to block this ability with FDA-approved drugs. They are determining whether there may be an existing compound that blocks C. neoformans from becoming germ cells, which could be a ready-to-go agent to prevent or treat fungal meningitis.

In addition to Brown, co-authors are Steven T. Denham, Brianna Brammer, Krystal Y. Chung, Morgan A. Wambaugh, Joseph M. Bednarek, Li Guo and Christian T. Moreau from U of U Health.

The research published as, “A dissemination-prone morphotype enhances extrapulmonary organ invasion by the fungus Cryptococcus neoformans” with support from the National Institutes of Health.

Reference:

1. Steven T. Denham, Brianna Brammer, Krystal Y. Chung, Morgan A. Wambaugh, Joseph M. Bednarek, Li Guo, Christian T. Moreau, Jessica CS Brown. A dissemination-prone morphotype enhances extrapulmonary organ invasion by Cryptococcus neoformans. Cell Host & Microbe, 2022; DOI: 10.1016/j.chom.2022.08.017

/Public release. This material from the original organization/author(s) may be of a chronological nature, edited for clarity, style and length. The views and opinions are those of the author(s). See in full here.