How Cryptococcus Bypasses the Blood Brain Barrier

Cordyceps is widely known as the zombie fungus because it likes to take over the brain functions of it victim. Often causing them to do things they normally wouldn't and leading to their demise.

But Cordyceps is not something that humans have to worry about. No, we have our own fungal nasties and one of the worst is Cryptococcus neoformans... I mean it has the word "Crypt" right there in its name! But what does C. neoformans have to do with Cordyceps?

Cryptococcus neoformans

Well, for starters, it infects the brain. In fact it is the causal agent of the most common fungal disease of the central nervous system. Cryptococcal meningoencephalitis is a very dangerous illness, and is actually a major cause of death in AIDS patients.

Our brain does have a good nervous system defense mechanism however; the Blood Brain Barrier. This series of tight junctions along its capillaries separates circulating blood from the nervous systems extracellular fluid. It acts basically as a gateway, restricting the diffusion of foreign particles and larger molecules into the cerebrospinal fluids, while allowing the small needed molecules (Oxygen, Hormones, etc.) through. This generally causes a pretty good barrier... but C. neoformans may have another thing in common with Cordyceps...

A study published in PLOS One finds C. neoformans takes control of the Endothelial cells that constitute the Blood Brain Barrier. Not in the grand way that Cordyceps does, but in a much simpler way. It causes the cell to induce fusogenic activity, and fuses into the very barrier meant to keep it at bay.

Cryptococcus neoformans-Derived Microvesicles Enhance the Pathogenesis of Fungal Brain Infection

You see, while C. neoformans grows and infects, it produces microvesicles which contain components for the fungus's capsule. This capsule is generally considered to be a major determiner of how virulent a strain is because those lacking it are avirulent. These vesicles travel across the cell wall of the fungus carrying the building blocks to bio-synthesize the capsule.

This study demonstrates the potential of these microvesicles in helping the pathogen traverse the blood brain barrier.

To start, the researchers fused a fluorescence protein into one of the most common proteins in C. neoformans derived microvesicles in order to directly view presence and concentration of their formation.

When human endothelial cells, such as those in the blood brain barrier, were exposed to the microvesicles ruffling of the plasma membrane was detected. As time progressed during incubation the fluorescence started increasing in the endothelial cells, suggesting that C. neoformans had invaded and was secreting more microvesicles within the cell.

Looking at density gradients to determine the mechanism for these effects the scientist discovered an uptake of lipid raft activity in the presence of the C. neoformans microvesicles. This means that when these microvesicles are around, the cell itself increases the ability for the invader to adhere to and travel across the membrane barrier.

In addition to this cell inducing, a secondary test to determine whether cell fusion took place was conducted. By dying multiple cell aliquots in distinct colors and presenting portions of them with microvesicles fusion would be detected by multi-fluorescent cells. And just as predicted, those not exposed did not fuse, while those presented with the invader did.

Tests run in vivo with mice demonstrated that by increasing amounts of these microvesicles, along with a C. neoformans infection, there was a significant increase of brain infection by the fungus. Thus the team demonstrated that Cryptococcus neoformans derived microvesicles play a significant role in brain invasion.

In this study, a glimpse of how devious pathogenic fungi  can be is revealed. While the more dramatic members, such as Cordyceps, garner picture worthy attention. The subterfuge practiced by Cryptococcus is just as deadly a form of mind control. More akin to a vampire glamoring you to inviting it in, than to outright controlling your body like a puppet.

A little too "In your face" for Cryptococcus.

Awesome Researchers:
Huang, S., Wu, C., Chang, Y., Kwon-Chung, K., Brown, R., & Jong, A. (2012). Cryptococcus neoformans-Derived Microvesicles Enhance the Pathogenesis of Fungal Brain Infection PLoS ONE, 7 (11) DOI: 10.1371/journal.pone.0048570
 
Photo Cred: By Dr. Graham Beards (Own work) [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons