Inheriting a tendency to Brain INfection

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Inheriting a Tendency to Brain Infection

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HERPES SIMPLEX ENCEPHALITIS PREDISPOSITION VIRUS VIROLOGY INHERITED

INFECTIOUS DISEASE

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New findings from researchers in France support the controversial idea

that an error in a single gene is enough to dramatically alter an

individual's susceptibility to certain infections.

Newswise - Might some infectious diseases run in families because one

inherits susceptibility to them? Although researchers generally agree

that an individual's genetic makeup contributes in subtle ways to

susceptibility to infectious disease, new findings from researchers in

France support the controversial idea that an error in a single gene is

enough to dramatically alter an individual's susceptibility to certain

infections.

Medical Institute (HHMI) international research scholar

Jean-t Casanova and Emmanuelle Jouanguy of the Necker Medical

School in Paris, along with other colleagues have identified a single

gene that predisposes individuals to herpes simplex encephalitis, an

infectious disease that tends to be extremely choosy about its victims.

In a paper published in the September 29, 2006 issue of the journal

Science, they describe two young patients who carry mutations in this

gene who are susceptible to the disease while being otherwise

immunologically normal. The paper was published in advance online.

As many as eight out of 10 adults are infected by the herpes simplex

virus. For most, the worst symptom is a cold sore, but in some

individuals, the virus causes inflammation of the brain that can lead to

mental retardation, epilepsy, or death. Until now, scientists have been

unable to identify any specific risk factors for the disease.

Five years ago, Casanova began to suspect that those who were

susceptible to the inflammatory brain disease were in fact genetically

predisposed to it. There was little published evidence that herpes

simplex encephalitis ran in families, which suggested to him that if a

genetic element was at work, it was probably recessive: an individual

had to carry two copies of the affected gene to show the predisposition.

Evidence he collected during an epidemiological survey in France

supported that idea. The survey, conducted with pediatric neurologist

Marc Tardieu of the Kremlin-Bicêtre hospital in Paris and genetic

epidemiologist t Abel of the Necker Medical School, revealed that

a significant proportion of patients with herpes simplex encephalitis

had parents who were blood relatives -often first or second cousins-and

were therefore at higher than normal risk of inheriting two copies of a

faulty gene.

In 2005, Casanova later identified a 15-year-old boy who developed brain

damage due to herpes simplex infection. Casanova found that the boy's

blood cells failed to produce an important immune signalling molecule,

type I interferon, when challenged with the virus in a laboratory flask.

At about the same time, Bruce Beutler of the Scripps Research Institute

in La Jolla, California created a mutant mouse that did not respond to

certain molecules that normally trigger cells to produce type I

interferon. The mouse turned out to be vulnerable to a range of

infections, but its susceptibility to herpes simplex had not been

tested. " Nevertheless,

" said Casanova, " the immunological abnormality perfectly matched that

found in our patient. "

Beutler's mouse carried a mutation in a gene called unc93b. The French

team sequenced the human counterpart, unc93b1, and found that their

patient carried two mutated copies of this gene. In early 2006, they

found a second, unrelated patient who had also inherited two mutated

copies of the gene-although the mutation in her case was different. She

had survived two episodes of the disease, which had left her partially

paralysed and mildly mentally retarded.

The link between interferon production and the disease suggests a new

strategy for treatment, Casanova said. " It's like giving insulin to a

diabetic patient, " he said. " You just replace the missing compound. "

Soon, children who come into the intensive care unit with herpes simplex

encephalitis may be treated with both the standard antiviral, acyclovir,

and with type I interferon, to replace the interferon they lack if they

have the mutation, said Casanova. That hasn't happened yet, although

patients susceptible to tuberculosis (TB) because of an inherited

deficiency in another interferon pathway have been successfully treated

with the interferon they lack. Based on the results in patients with TB,

Casanova hopes the combined treatment could dramatically accelerate

recovery from herpes simplex encephalitis, and thereby also limit

potential brain damage.

Casanova believes there are likely other genes that predispose people to

infectious diseases, and that some of them may be inherited in a

dominant fashion. That is, an individual need inherit only one copy of

the mutation to show the predisposition. In his opinion, scientists will

increasingly need to view common infectious diseases through the lens of

such primary immunodeficiencies.

" Understanding the genetic basis of the failure of the immune system

should make it possible to devise novel ways to make it succeed, " he said.

Since the mid-1950s, most infectious disease researchers have believed

that the genetic components of infectious disease are complex, involving

different genetic variants interacting with each other and with the

environment in subtle ways that add up to an overall predisposition or

resistance.

However, Levin, professor of pediatrics and international child

health at Imperial College, London, does not think the two theories are

mutually exclusive. " We strongly suspect that rare, highly deleterious

mutations may co-exist with common polymorphisms in many infectious

diseases, " he said.

Jean-t Casanova is in the U.S. this week, presenting this research

at the HHMI international research scholars' meeting at HHMI's new

Janelia Farm Research Campus in northern Virginia.

HHMI's international research scholars are scientists of the highest

quality whose research HHMI supports in their home countries. The

program links them with each other and with other HHMI researchers to

create an international network of outstanding scientists. Since 1991,

the Institute has awarded more than $100 million in grants to scientists

worldwide.

A nonprofit medical research organization, the Medical

Institute was established in 1953 by the aviator-industrialist. The

Institute, headquartered in Chevy Chase, land, is one of the largest

philanthropies in the world, with an endowment of $16.3 billion at the

close of its 2006 fiscal year. HHMI spent $478 million in support of

biomedical research and $81 million for support of a variety of science

education and other grants programs in fiscal 2006