Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSD Researchers Decipher Function Of Blood-Brain Barrier in Bacterial Meningitis

03.09.2003


The first line of defense used by the human blood-brain barrier in response to bacterial meningitis is described by researchers at the University of California, San Diego (UCSD) School of Medicine in a study published in the September 2, 2003 issue of The Journal of Clinical Investigation. The scientists also describe two bacterial factors specific to the meningitis pathogen that thwart the normal protective role of the blood-brain barrier, leading to serious infection.


Schematic illustration of the blood-brain barrier response to the bacterium.Group B Streptococcus during newborn meningitis. Endothelial cells activate genes and produce protein factors that summon white blood cells to the brain to help fight the infection.


Kelly Doran, Ph.D., lead author



Composed of a layer of blood vessels called brain microvascular endothelial cells (BMEC), the blood-brain barrier separates the brain and its surrounding tissues from the circulating blood, tightly regulating the flow of nutrients and molecules and thereby maintaining the proper biochemical conditions for normal brain function.

Bacterial meningitis, a serious brain infection, can develop rapidly into a life-threatening infection even in previously healthy children or adults. Bacteria-producing meningitis enter the human bloodstream, are carried toward the brain, and somehow manage to cross the defensive line of the blood-brain barrier.


Using an experimental blood-brain barrier established by growing layers of human BMEC in tissue culture plates, the UCSD team observed that a specific set of 80 genes in the blood-brain barrier were activated when exposed to the pathogen Group B Streptococcus (GBS), the leading cause of bacterial meningitis in human newborn infants. These genes released proteins that mobilized human white blood cells called neutrophils, which are attracted to sites of infection.

Lead author Kelly Doran, Ph.D., assistant adjunct professor of pediatrics in the UCSD Division of Infectious Diseases, said “these findings demonstrate a novel function of the blood-brain barrier, to act as a sentry that detects the threat of a bacterial pathogen and responds by triggering an immune response to clear the infection.”

According to senior author Victor Nizet, M.D., associate professor of pediatrics, UCSD Division of Infectious Diseases and an attending physician at Children’s Hospital, San Diego, “the experiments also explain the basic mechanisms underlying the critical test used by physicians to make an early diagnosis of bacterial meningitis, namely the presence of abundant neutrophils in the fluid collected from the patient by the procedure known as a spinal tap.”

Although the blood-brain barrier effectively blocks the vast majority of circulating bacteria from entering the brain, its defensive function fails in bacterial meningitis infections. To understand how specific virulence properties of the GBS pathogen affect the blood-brain barrier immune response, the UCSD team developed mutant strains of GBS.

Hypothesizing that the capsule coating the surface of the GBS pathogen decreases the ability of the white blood cells and blood-brain barrier cells to recognize the bacteria as foreign, the researchers developed a GBS bacteria without a capsule. They discovered that the mutant was more easily recognized by the blood-brain barrier, which triggered a protective immune response.

“Thus, the role of the capsule is to cloak the bacteria, resulting in a weakened initial immune response that allows the pathogen to survive in the blood and produce an infection within the small blood vessels of the brain,” Nizet said. “It appears that the normal GBS with a capsule may represent a form of ‘molecular mimicry,’ where the bacteria disguises itself to look more like the host and avoid immune recognition.”

In a second test, the researchers developed a GBS mutant that lacked a potent cell-damaging toxin called beta-hemolysin/cytolysin. Mouse models infected with this mutant bacteria produced less meningitis than mice given normal GBS bacteria.

The researchers determined that after the GBS bacteria reach high concentrations in the blood-brain barrier, the action of the beta-hemolysin/cytolysin toxin injures the endothelial cells, breaks down the blood-brain barrier, and provokes the neutrophil inflammatory response that is the hallmark of bacterial meningitis. But by then it is too late as the bacteria are already entering the brain tissues. In fact, the activated neutrophils produce toxic compounds in an attempt to kill the bacteria, and these compounds also contribute to the brain injury of meningitis.

The UCSD team is continuing its studies to learn more about the role of pathogens in brain infection.

“We believe our ongoing studies of the interactions of the blood-brain barrier with bacterial pathogens will help uncover basic biologic principles that will lead to improved therapies for meningitis and other central nervous system infections,” Doran said.

George Liu, M.D., Ph.D., infectious diseases fellow, UCSD Department of Pediatrics, also contributed to the study. The work was funded by a Burroughs Wellcome Foundation Career Award to Doran, a Howard Hughes Medical Institute Postdoctoral Fellowship to Liu, an Edward J. Mallinckrodt Scholar Award to Nizet, the National Institutes of Health, and the United Cerebral Palsy Research Foundation.



News Media Contact:
Sue Pondrom
619-543-6163
spondrom@ucsd.edu

Sue Pondrom | UCSD
Further information:
http://health.ucsd.edu/news/2003/09_02_Nizet.html
http://health.ucsd.edu/news/

More articles from Health and Medicine:

nachricht Nanotubes are beacons in cancer-imaging technique
23.05.2016 | Rice University

nachricht More light on cancer
20.05.2016 | Lomonosov Moscow State University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Worldwide Success of Tyrolean Wastewater Treatment Technology

A biological and energy-efficient process, developed and patented by the University of Innsbruck, converts nitrogen compounds in wastewater treatment facilities into harmless atmospheric nitrogen gas. This innovative technology is now being refined and marketed jointly with the United States’ DC Water and Sewer Authority (DC Water). The largest DEMON®-system in a wastewater treatment plant is currently being built in Washington, DC.

The DEMON®-system was developed and patented by the University of Innsbruck 11 years ago. Today this successful technology has been implemented in about 70...

Im Focus: Computational high-throughput screening finds hard magnets containing less rare earth elements

Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.

The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...

Im Focus: Atomic precision: technologies for the next-but-one generation of microchips

In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.

In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...

Im Focus: Researchers demonstrate size quantization of Dirac fermions in graphene

Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices

Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.

Im Focus: Graphene: A quantum of current

When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene

In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking 4.0: International Laser Technology Congress AKL’16 Shows New Ways of Cooperations

24.05.2016 | Event News

Challenges of rural labor markets

20.05.2016 | Event News

International expert meeting “Health Business Connect” in France

19.05.2016 | Event News

 
Latest News

11 million Euros for research into magnetic field sensors for medical diagnostics

27.05.2016 | Awards Funding

Fungi – a promising source of chemical diversity

27.05.2016 | Life Sciences

New Model of T Cell Activation

27.05.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>