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Fungal protein found to cross blood-brain barrier
Date:6/12/2014

over how C. neoformans breaches the blood-brain barrier, the investigators isolated candidate proteins from the cryptococcal cell surface. One was a previously uncharacterized metalloprotease that they named Mpr1. (A protease is an enzyme a specialized protein that promotes a chemical reaction; a metalloprotease contains a metal ion in this case zinc that is essential for its activity.) The M36 class of metalloproteases to which Mpr1 belongs is unique to fungi and does not occur in mammalian cells.

The investigators next artificially generated a strain of C. neoformans that lacked Mpr1 on the cell surface. Unlike the normal wild-type C. neoformans, the strain without Mpr1 could not cross an artificial model of the human blood-brain barrier.

They next took a strain of common baking yeast Saccharomyces cerevisiae that does not cross the blood-brain barrier and does not normally express Mpr1, and modified it to express Mpr1 on its cell surface. This strain then gained the ability to cross the blood-brain barrier model.

Investigators then infected mice with either the C. neoformans that lacked Mpr1 or the wild-type strain by injecting the organisms into their bloodstream. Comparing the brain pathology of mice 48 hours later, they found numerous cryptococci-filled cysts throughout the brain tissue of mice infected with the wild-type strain; these lesions were undetectable in those infected with the strain lacking Mpr1. In another experiment, after 37 days of being infected by the inhalation route, 85 percent of the mice exposed to the wild-type C. neoformans had died, while all of those given the fungus without Mpr1 were alive.

"Our studies are the first clear demonstration of a specific role for a fungal protease in invading the central nervous system," said Gelli. "The details of exactly how it crosses is an important new area under investigation."

New targeted therapie
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Contact: Carole Gan
carole.gan@ucdmc.ucdavis.edu
916-734-9047
University of California - Davis Health System
Source:Eurekalert

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