monocytes & neutrophils in: Fatal Brain Injury From Acute Viral Meningitis

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New Cause Of Fatal Brain Injury From Acute Viral Meningitis

http://www.sciencedaily.com/releases/2008/11/081117131719.htm

ScienceDaily (Nov. 21, 2008) --- What was once thought to be the culprit

responsible for fatal brain damage in acute viral meningitis has now

been found to be only an accomplice, say researchers at the Scripps

Research Institute.

In a November 16 advance, online publication of the journal Nature, the

researchers say their discovery revamps common beliefs about how such

potentially lethal infections may be ravaging the brain and suggests the

possibility of new treatments.

" This is a paradigm shift in how we think about some forms of meningitis

and possibly other infections, " says the study's lead investigator,

Dorian B. McGavern, Ph.D., an associate professor in the Department of

Immunology at Scripps Research. " What we thought were the killers are

actually immune cells that recruit other accessory cells that then drive

the disease. If we can find ways to block recruitment of the cells that

actually do the damage into the brain, we may be able to limit the

impact of the virus. "

Meningitis occurs when the membrane (the meninges) that covers and

protects the spinal cord and brain become inflamed, usually due to a

bacterial or viral infection. The condition is considered a medical

emergency because it can lead to an inflammatory response that results

in brain swelling, seizures, blood clotting, epilepsy, or other

complications, sometimes resulting in death. Many viruses can cause

meningitis.

In this study, investigators looked at what happens in the brain of mice

exposed to lymphocytic choriomeningitis virus (LCMV), a virus that can

also infect humans, but which does not cause a lot of damage on its own.

Instead, the virus pushes an immune response that, in itself, is

damaging because it results in " leaky " blood vessels in the meninges at

the blood-brain border.

" We use this mild virus because all the damage produced in the brain is

caused by the immune system, " McGavern says. " While other viruses are

more pathologic, they all produce an immune response. "

The researchers developed a unique way to " watch " what happens in the

brain of mice infected with LCMV by tagging immune cells known as

cytotoxic T lymphocytes (CTLs)---also known as killer T cells---with

proteins that shine a fluorescent green. These cells, which the

researchers knew reacted to LCMV, are the immune system fighters

previously thought to be responsible for battling the virus and damaging

the brain in the process.

When the researchers injected the tagged killer T cells into the mice,

followed one day later with a dose of the virus, then a dye to visualize

blood vessels, the scientist found that they could use two-photon

microscopy to see what was happening 300-400 microns below the surface

of the skull in the brain. Sure enough, the scientists could see blood

vessels breaking down as meningitis developed and progressed, but the

tagged killer T cells did not appear to be the direct cause of the

vascular damage.

" We thought the disease depended on these killer T cells, but they

didn't seem to be associated with any of the damage we were seeing, "

McGavern says.

The researchers then tagged other populations of immune cells:

monocytes, which usually clean up and repair damage, and neutrophils,

which may help with antiviral immunity. To their surprise, the

scientists saw that these cells flooded the brain after LCMV infection,

and were associated with significant damage to blood vessels in the

brain's membrane.

" The vessels just start exploding, " McGavern says. " This tells us that

killer T cells recruit monocytes and neutrophils that actually produce

the pathology we see with meningitis. What we thought were the cells

responsible actually only recruit accomplices who commit the crime. "

The researchers don't know exactly why monocytes and neutrophils are

called to sites of infection by killer T cells, or how they produce such

damage in meningitis. They theorize that the breakdown of blood vessels

may be the result of these cells' attempts to move quickly out of the

blood system into tissue within the confined space of the brain.

Now, however, the scientists do have a new avenue to explore for

possible treatments for the deadly disease.

Co-authors of the paper, " Myelomonocytic cell recruitment causes fatal

CNS vascular injury during acute viral meningitis, " include Silvia S.

Kang from Scripps Research, and Jiyun V. Kim and L. , from

the New York University School of Medicine. The study was funded by

grants from the National Institutes of Health, The Burroughs Wellcome

Fund, and the Dana Foundation.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest

independent, non-profit biomedical research organizations, at the

forefront of basic biomedical science that seeks to comprehend the most

fundamental processes of life. Scripps Research is internationally

recognized for its discoveries in immunology, molecular and cellular

biology, chemistry, neurosciences, autoimmune, cardiovascular, and

infectious diseases, and synthetic vaccine development. Established in

its current configuration in 1961, it employs approximately 3,000

scientists, postdoctoral fellows, scientific and other technicians,

doctoral degree graduate students, and administrative and technical

support personnel. Scripps Research is headquartered in La Jolla,

California. It also includes Scripps Florida, whose researchers focus on

basic biomedical science, drug discovery, and technology development.

Scripps Florida is currently in the process of moving from temporary

facilities to its permanent campus in Jupiter, Florida. Dedication

ceremonies for the new campus will be held in February 2009.

Adapted from materials provided by Scripps Research Institute, via

EurekAlert!, a service of AAAS.

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*1: *Nature. <javascript:AL_get(this, 'jour', 'Nature.');> 2008 Nov 16.

[Epub ahead of print]Click here to read

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Myelomonocytic cell recruitment causes fatal CNS vascular injury

during acute viral meningitis.

*Kim JV*

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[1] Program in Molecular Pathogenesis, Helen L. and S. Kimmel

Center for Biology and Medicine, Skirball Institute of Biomolecular

Medicine, New York University School of Medicine, New York, New York

10016, USA [2] These authors contributed equally to this work.

Lymphocytic choriomeningitis virus infection of the mouse central

nervous system (CNS) elicits fatal immunopathology through

blood-brain barrier breakdown and convulsive seizures. Although

lymphocytic-choriomeningitis-virus-specific cytotoxic T lymphocytes

(CTLs) are essential for disease, their mechanism of action is not

known. To gain insights into disease pathogenesis, we observed the

dynamics of immune cells in the meninges by two-photon microscopy.

Here we report visualization of motile CTLs and massive secondary

recruitment of pathogenic monocytes and neutrophils that were

required for vascular leakage and acute lethality. CTLs expressed

multiple chemoattractants capable of recruiting myelomonocytic

cells. We conclude that a CD8(+) T-cell-dependent disorder can

proceed in the absence of direct T-cell effector mechanisms and rely

instead on CTL-recruited myelomonocytic cells.

PMID: 19011611