Scientists discover that a fungus shrinks in size to infect the brain

Scientists from the University of Utah Health have found that Cryptococcus neoformans, a dangerous fungus, alter in size after it enters a body, increasing the likelihood of infection, according to a press release published by the institution.

The fungus may be found in a variety of settings and shows the same adaptability inside the body once inhaled, moving from the lungs via the bloodstream to other organs.

Once entered the body, it can cause a variety of symptoms such as the rare but potentially deadly fungal meningitis, which causes swelling of the brain in people with weakened immune systems.

“Cryptococcus cells in the lungs are very diverse with different sizes and different appearances. So, when my graduate student showed me pictures of the uniformity of cells from the brain, I was shocked," says pathologist Jessica Brown, from the University of Utah.

"It suggested that there was some very strong reason why only this population of cells were making it that far into the body."

Adapting to challenging micro-environments

Brown’s fascination with the fungus was due to its ability to survive in different habitats. If inadvertently inhaled, it can spread from the lungs to the bloodstream, brain, and other organs, each of which has a challenging micro-environment of its own.

Previous findings show that the fungus multiplies to ten times its usual size in order to survive in the lungs, presumably growing too big for the host immune system to kill. Nevertheless, fungal cells are significantly smaller in other parts of the body.

In this direction, Brown wondered if the cells’ extra-small size could be another type of advantage. Perhaps that characteristic helps them colonize other organs, such as the brain.

To investigate why cells of a specific size were found so deep in the host territory, the researchers infected mice with various sizes of C. neoformans and found that, compared to medium and large cells, the smallest prefer infecting the brain.

These small cells also differed from the others with the unique features on their surface that were similarly important for accessing the brain. It's been suggested by the researchers that these "seed cells" aren't only the shrunk-down versions of the fungus, but something quite different instead.

Based on the scientists' experiments these changes are estimated to be powered by phosphate. Phosphate, released from host cells when tissues are damaged during infection, seems to be the catalyst for the fungus being able to shapeshift, which might help it infect its hosts and reach the brain.

"We think that selective pressures from environmental niches like pigeon guano are somehow able to confer to C. neoformans the ability to infect mammals," says Brown.

Regardless of how the fungus acquired its spreading capacity, Brown's team is currently attempting to disable it via FDA-approved drugs. They are investigating if a substance that prevents C. neoformans from developing into seed cells could already exist and be used as a treatment for preventing or treating fungal meningitis.

The research was published in the peer-reviewed journal Cell Host & Microbe.

Abstract:

Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that the formation of a small C. neoformans morphotype—called “seed” cells due to their colonizing ability—is critical for extrapulmonary organ entry. Seed cells exhibit changes in fungal cell size and surface expression that result in an enhanced macrophage update. Seed cell formation is triggered by environmental factors, including C. neoformans’ environmental niche, and pigeon guano with phosphate plays a central role. Seed cells show the enhanced expression of phosphate acquisition genes, and mutants unable to acquire phosphate fail to adopt the seed cell morphotype. Additionally, phosphate can be released by tissue damage, potentially establishing a feed-forward loop of seed cell formation and dissemination. Thus, C. neoformans’ size variation represent inducible morphotypes that change host interactions to facilitate microbe spread.