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mutations of a particular gene increase a person's susceptibility to
infection and death from bacterial meningitis.
The findings, which appear in the April 28 online issue of the
Proceedings of the National Academy of Sciences, may help
prevent the disease in people who have one or more of the mutations
and are at high risk.
The study gives more details of an increasingly complex picture.
"This is just a piece of the pie. This is not the whole thing," says
Dr. Rodrigo Hasbun, an associate professor of medicine at Tulane
University School of Medicine in New Orleans.
Meningitis is an inflammation of the lining of the brain and the
spinal cord. Most commonly, it is caused by a bacteria or virus.
Bacterial meningitis is the more serious form of the disease and is
usually caused by the meningococcal or the pneumococcal bacteria.
This study looked at the meningococcal form of the disease.
In extreme cases, the infection can progress to sepsis, which
means it spreads to many parts of the body and can cause death or
life-long debilitation. Meningococcal sepsis affects more than 2,500
people a year in the United States, about half of whom are under the
age of 2. Some 12 percent of those who contract the disease die of
it.
While many individuals harbor the bacteria that causes meningitis
in their nose, throat and upper respiratory tract, only a tiny
proportion actually develop the disease.
Scientists have already recognized certain factors that affect
susceptibility to the disease.
"The first thing that has been well known for several years is
complement deficiency," Hasbun explains. "Patients that have
genetically deficient complement are definitely at higher risk of
having the disease."
Complements work with antibodies to kill certain types of
bacteria. Without complements, antibodies simply can't do their job.
There is already a test in existence to determine who has this
deficiency.
The second area is "mannose-binding lectin," a protein that
activates the complement to bind to the antibody. Again, when this
is missing or defective, patients cannot mount an effective defense.
The current study describes a third aspect of innate immunity.
Individuals who have their spleen taken out are also at risk, but
that is considered acquired immunity.
The authors of the paper analyzed genetic information from more
than 200 English, Dutch and American children with meningococcal
disease. Then, using a special software designed just for this
purpose, they sequenced the entire TLR4 (toll-like receptor 4) gene
from each patient, looking for aberrations.
There were clear points of difference in the TLR4 genes of the
people who had contracted sepsis compared to healthy controls. The
TLR4 gene "normally detects endotoxin, an essential structural
component of gram-negative bacteria [like the meningococcus],"
explains Dr. Bruce Beutler, senior author of the paper and a
professor of immunology at the Scripps Research Institute in La
Jolla, Calif. "Without it, the body does not recognize that there is
an infection at an early stage, and cannot overcome it."
When bacteria infect the body, they trigger the immune system to
recruit white blood cells to fight the pathogens by producing
inflammation. If the infection is particularly widespread, the
endotoxin levels might be so high that they produce a lethal level
of inflammation. This can result in sepsis.
Individuals with TLR4 mutations can no longer detect the presence
of gram-negative bacteria. "When they can't sense that type of
bacteria in the bloodstream, it's not going to be able to send its
soldiers to fight it," Hasbun says.
"This is the first time that mutations in any of the toll-like
receptors (of which there are ten in humans) have been clearly
implicated in a disease," Beutler says.
Broad-spectrum antibiotics are usually used to fight bacterial
meningitis but may not be effective if the infection is too severe
or widespread. A meningococcal vaccine does exist, but it's not
feasible to administer it to everyone, given the small number of
people who contract the disease. A test for complement deficiencies
can identify some people who should get a vaccine. The current
findings may pave the way for another test.
"Hopefully, the benefit will be a nice, easy, not costly test
that we could use to try to identify who's at risk for having this
type of infection so we can vaccinate those patients," Hasbun says.
"Currently it's not cost-effective to vaccinate everybody because
the incidence is so low, but if we could identify who's at risk, we
could just vaccinate them."
"Some day, as sequencing technology advances, it might be
feasible to determine the genotype of individuals at all of the
toll-like receptor loci (including TLR4) and at other loci that
might produce susceptibility to infection," Beutler adds. "One could
then try to protect people who are at risk through a program of
vaccination or antibiotic treatment before a serious infection has a
chance to start."
More information
For more on meningitis, visit the U.S.
Centers for Disease Control and Prevention,
the
National Meningitis Association, or the
Meningitis
Foundation of America.
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