The investigators isolated the protein that is responsible for the fungus' ability to cross the blood-brain barrier -
In a remarkable series of experiments on a fungus that causes meningitis cryptococcosis , a fatal infection of the membranes covering the spinal cord and brain, UC Davis researchers have isolated a protein that appears to be responsible for the fungus' ability to cross the blood circulation in the brain
discovery - published time:. June 3 in MBIO, open access, peer-reviewed journal of the American Society for Microbiology - has important implications for the development of more effective treatment for Cryptococcus neoformans, the cause status, and other brain infections, and for brain cancers are difficult to treat with conventional drugs.
"This study fills an important gap in our understanding of how C. neoformans crosses the blood-brain barrier and causes meningitis, "said Angie Gelli, associate professor of pharmacology at UC Davis and principal investigator of the study. "We hope that our results will lead to improved treatment of this fungal disease and other central nervous system diseases."
Normally, the brain is protected against bacterial, viral and fungal pathogens in blood by a tightly packed layer of endothelial cells lining the capillaries of the central nervous system - called the blood-brain barrier. Relatively few organizations - and drugs that could fight against brain infections or cancers. - Can violate this barrier
The fungus studied in this research causes meningoencephalitis cryptococcosis, a usually fatal infection of the brain that affects every year about 1 million people worldwide, mostly those who have an immune system weakened. People usually first develop an infection in the lungs after inhalation of fungal spores of C. neoformans in soil or droppings pigeons. The pathogen then spreads to the brain and other organs.
single protein identified
In an effort to discover how C. neoformans exceed the blood-brain barrier, researchers candidate proteins isolated cryptococcosis the cell surface. One was an uncharacterized metalloproteinase they named MPR1. (A protease is an enzyme - a specialized protein - which promotes a chemical reaction ;. A metalloprotease contains a metal ion - in this case, zinc - which is essential for its activity) The M36 class of metalloproteases which belongs MPR1 is unique to fungi and does not occur in mammalian cells.
researchers then artificially generated a strain of C. neoformans which do not have MPR1 on the cell surface. Unlike normal C. neoformans wild type, strain without MPR1 could not cross an artificial model of the human blood-brain barrier
They then took a common baker's yeast strain -. Saccharomyces cerevisiae - that cross the blood-brain barrier and does not normally express MPR1 and modified to express MPR1 on its cell surface. This strain was then acquired the ability to cross the blood-brain barrier model.
mouse investigators then be infected with C. neoformans that lacked MPR1 or the wild type strain by injecting organisms in their blood. Comparing the mouse brain pathology 48 hours later, they found numerous cryptococcal filled cysts around the brain tissue of mice infected with wild-type strain; these lesions were undetectable in people infected with the strain lacking MPR1. In another experiment, after 37 days of infection by the inhalation route, 85 percent of mice exposed to wild C. neoformans had died, while those given the fungus without MPR1 were alive.
"Our studies are the first clear demonstration of a specific role for a fungal protease invade the central nervous system," Gelli said. "The details of exactly how it crosses is an important new field under investigation . "
new targeted therapies possible
According to Gelli, their discovery has important therapeutic potential in two important mechanisms Either MPR1 -. or aspect of the mechanism by which it crosses the blood-barrier brain - could be a target for new drugs for the treatment of meningitis caused by C. neoformans in a person who develops a pulmonary cryptococcosis infection, such treatment would ideally make the fungus less likely to enter the brain and lead to. a rapidly fatal meningitis.
Second, MPR1 could be developed as part of a drug delivery vehicle for brain infections and cancers. Antibiotic drug or fight against cancer which is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing MPR1, allowing him to hitch a ride and deliver products to where it is needed .
"the greatest obstacle to the treatment of many cancers of the brain and infections becomes good drugs across the blood-brain barrier," said Gelli. "If we could design an effective distribution system in the brain, the impact would be huge for the treatment of some of these terrible diseases. "
The group of Gelli is currently pursuing such a nanoparticle drug delivery system using MPR1. They also study further the molecular mechanism by which exact MPR1 violates the blood-brain barrier.
EmoticonEmoticon