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

(SACRAMENTO, Calif.) In a remarkable series of experiments on a fungus that causes cryptococcal meningitis, a deadly infection of the membranes that cover the spinal cord and brain, investigators at UC Davis have isolated a protein that appears to be responsible for the fungus' ability to cross from the bloodstream into the brain.

The discovery published online June 3 in mBio, the open-access, peer-reviewed journal of the American Society for Microbiology has important implications for developing a more effective treatment for Cryptococcus neoformans, the cause of the condition, and other brain infections, as well as for brain cancers that are difficult to treat with conventional medications.

"This study fills a significant 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. "It is our hope that our findings will lead to improved treatment for this fungal disease as well as other diseases of the central nervous system."

Normally the brain is protected from bacterial, viral and fungal pathogens in the bloodstream by a tightly packed layer of endothelial cells lining capillaries within the central nervous system the so-called blood-brain barrier. Relatively few organisms and drugs that could fight brain infections or cancers can breach this protective barrier.

The fungus studied in this research causes cryptococcal meningoencephalitis, a usually fatal brain infection that annually affects some 1 million people worldwide, most often those with an impaired immune system. People typically first develop an infection in the lungs after inhalation of the fungal spores of C. neoformans in soil or pigeon droppings. The pathogen then spreads to the brain and other organs.

Unique protein identified

In an effort to discover 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 therapies possible

According to Gelli, their discovery has significant therapeutic potential via two important mechanisms. Either Mpr1 or an aspect of the mechanism by which it crosses the blood-brain barrier could be a target of new drugs for treating meningitis caused by C. neoformans. In a person who develops cryptococcal lung infection, such a treatment would ideally make the fungus less likely to enter the brain and lead to a rapidly fatal meningitis.

Secondly, Mpr1 could be developed as part of a drug-delivery vehicle for brain infections and cancers. An antibiotic or cancer-fighting drug that is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing Mpr1, allowing it to hitch a ride and deliver its goods to where it is needed.

"The biggest obstacle to treating many brain cancers and infections is getting good drugs through the blood-brain barrier," said Gelli. "If we could design an effective delivery system into the brain, the impact would be enormous for treating some of these terrible diseases."

Gelli's group is currently pursuing such a nanoparticle drug-delivery system using Mpr1. They are also further investigating the exact molecular mechanism by which Mpr1 breaches the blood-brain barrier.


'/>"/>

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

Related medicine news :

1. Children failing asthma therapy may have severe asthma with fungal sensitization
2. Texas A&M biologists prove ZOLOFT packs potential to fight fungal meningitis
3. Cases Linked to Fungal Meningitis Now Number 328
4. Fungal Meningitis Outbreak Toll Now 28 Dead, 363 Sickened
5. Flesh-Eating Fungal Infection Can Follow Natural Disasters, Study Finds
6. New Topical Solution for fungal infection by Zeta Clear released to Cure Toenail and Fingernail fungus
7. Valley Fever Fungal Infection on Rise in Southwest
8. Combo Therapy Helps Knock Out Fungal Meningitis
9. Blood Test May Catch Deadly Fungal Infection Quickly
10. Study finds nearly 5 million asthmatics worldwide could benefit from antifungal therapy
11. New €6.1million project to develop new antifungal agents to treat resistant fungal infections
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/28/2017)... Pensacola, FL (PRWEB) , ... April 28, 2017 ... ... Tampa, Florida are conducting a pilot study of ActiGraph’s CentrePoint Data ... ActiGraph is a leading provider of clinical-grade wearable activity and sleep monitoring solutions ...
(Date:4/28/2017)... ... April 28, 2017 , ... NuevaCare, a leading home care ... Millbrae, Burlingame, and Palo Alto, is proud to announce information upgrades to its blog ... and read organized content on topics such as home care (generally) as well as ...
(Date:4/27/2017)... (PRWEB) , ... April 27, 2017 , ... ... nation’s leading respiratory hospital, based in Denver, Colorado, announced an agreement to create ... by the continuing support of the Jane and Leonard Korman Family Foundation. The ...
(Date:4/27/2017)... ... April 27, 2017 , ... The American ... 2017 Public Leadership in Neurology Award (PLINA). The couple joins a prestigious list ... Vice President Walter Mondale, actor Michael J. Fox and former U.S. Attorney General ...
(Date:4/27/2017)... ... , ... Offering the purest product of its kind, Swissx Labs AG has ... than the market has seen before. Swissx uses proprietary strains of hemp plants grown ... process for extraction, to produce its CBD oil--maximizing its benefits for health and wellness. ...
Breaking Medicine News(10 mins):
(Date:4/19/2017)... April 19, 2017 /PRNewswire/ - CRH Medical Corporation (TSX: CRH) (NYSE MKT: CRHM) ... & Co. Healthcare Investor Conference 2017 at the Sheraton Hotel in ... , Chief Executive Officer of the Company is scheduled to present ... Richard Bear and the Chairman of the Board, Tony ... ...
(Date:4/19/2017)... NEW YORK , April 19, 2017 /PRNewswire/ ... This report on the prostate cancer ... of the global market. Increasing prevalence of prostate ... as innovation in the development of new drugs ... hormone-refractory prostate cancer drug due to lesser side ...
(Date:4/19/2017)... BOSTON , April 19, 2017  New research provides ... with advanced Parkinson,s, according to a study released today that ... 69th Annual Meeting in Boston , ... comes to the treatment of Parkinson,s disease, the oral drug ... of life and longevity. But as the disease progresses, the ...
Breaking Medicine Technology: