When Cryptococcus neoformans kills, as it does more than half a million times every year, it does so by infecting the central nervous system. Its victims, mostly AIDS patients and others with weakened immune systems, normally succumb to painful fungal meningitis, their brains overloaded with invasive fungal cells. As we reported back in April, scientists have discovered that the pathogen reaches the central nervous system by hitching a ride on immune cells—Trojan Horse style. Now, scientists have discovered the trick that it plays to break through the blood-brain barrier, which is a protective sheath that separates circulating blood from the fluid that floats around in the brain.
And, in a satisfying upshot of research into the pathogen's brain-invading modus operandi, described this month in mBio, the discovery promises more than simply improving treatment for Crypto patients. The fungal technique could eventually be co-opted by doctors, who could potentially use it as a tool for delivering medicine into the brain capable of relieving a range of neurological ailments.
The fungal technique could eventually be co-opted by doctors, who could potentially use it as a tool for delivering medicine into the brain capable of relieving a range of neurological ailments.
Scientists from the University of California-Davis and San Diego State University discovered an enzyme produced by C. neoformans, which they called Mpr1. The name comes from the technical name given to this type of enzyme—it's a variety of metalloprotease known as fungalysin.
Suspecting that this enzyme might be involved in helping the fungus slip through the blood-brain barrier, the scientists genetically engineered a strain of C. neoformans that was unable to produce it. They then grew human brain endothelial cells—found in the human blood-brain barrier—in a laboratory and compared the barrier-crossing abilities of wild strains to those of their engineered strains. "Significantly fewer" cells of the engineered variety broke through the simulated barrier, when compared with the wild strains, the authors wrote in the paper.
Then the scientists injected mice with the same strains. After 37 days of infection, all of the mice infected with the genetically engineered strain were still alive, but 85 percent of those infected with the wild strain were dead. Dissections revealed that all of the mice had similar fungal loads in their heart, kidneys, and lungs, but that the mice infected with the engineered strain had "significantly reduced" loads in their central nervous systems.
For good measure, the scientists also engineered a strain of baker's yeast to produce Mpr1, producing a freak yeast that was suddenly capable of crossing the simulated blood-brain barrier in their laboratory experiments.
"We aim to find inhibitors of Mpr1 as a means to develop drugs that will prevent the fungus from entering the brain," says Angie Gelli, an associate professor at U.C. Davis involved with the research.
Another "idea is to attach the Mpr1 to a drug-loaded nanocarrier to create a platform technology that will allow the delivery of therapeutics across the blood-brain barrier for the treatment of brain disorders," she says. "We're currently developing this technology."