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【medical-news】颅内感染的遗传趋势

Inheriting a Tendency to Brain Infection
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.

Howard Hughes Medical Institute (HHMI) international research scholar Jean-Laurent 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 8 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 Laurent 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 signaling 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 paralyzed 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.

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作者:admin@医学,生命科学    2011-08-14 05:13
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