Genetics takes the risky guesswork out of sepsis
by Apoorva Mandavilli, BioMedNet News
(http://news.bmn.com/news/story?day=020201&story=2)
A California scientist today revealed a group of mutations that seem to predispose people to meningococcal infection. The revelation could lead to interventions that forestall meningococcal sepsis by addressing it upstream, rather than leaping in as soon as possible after its onset.
"One of the great minefields in modern medicine has been sepsis," pointed out Ralph Nachman, chairman of the Department of Medicine at Cornell University in New York, where immunologist Bruce Beutler today revealed genetic variations that may determine who becomes afflicted with an infectious disease and who does not.
"Sepsis has been a minefield, because people have always tried to block it after the fact," noted Beutler. His discovery that susceptibility to meningococcal infection corresponds with genetic variations in the TLR family of genes, sentinel receptors in identifying infectious agents, may lead to ways to predict sepsis and avert it. Because the data are unpublished, Beutler declined to reveal the exact location of the mutations.
Studies more than a decade old have established that, although premature death in general appears to be heritable, it is significantly more heritable for deaths due to infection than for, say, heart disease or cancer. "That strikes me as remarkable, given the quintessentially environmental nature of infection," observed Beutler, who is professor of immunology at the Scripps Research Institute in La Jolla, California.
But the quest to isolate the relevant genes has been long and arduous. As early as 1894, scientists identified lipopolysaccharides (LPS), the principal component of the outer membrane in gram-negative bacteria, as responsible for inducing sepsis. For most of the 20th century, LPS, or endotoxin as it was termed, was the prototype for all microbial toxins. But it wasn't until 1998, after years of painstaking positional cloning, that scientists identified the host receptor for LPS.
Beutler, who was then at the University of Texas Southwestern Medical Center, identified the Toll-like receptor TLR4 as a "biological bottleneck" - a single gene product responsible for sensing endotoxin. Since then, gene knockout studies have identified TLR2 as a receptor for peptidoglycan and lipopeptides, and TLR9 as a receptor for unmethylated DNA.
There are now 10 known TLR genes; researchers have also characterized a superfamily, defined by a Toll/IL-1 receptor (TIR) domain, as a group of receptors that participate in host responses to injury and infection.
The TLR4 protein resembles the Drosophila protein Toll, which is critical in both embryonic development and in the fly's innate immunity against fungal infections. Mutations in TLR4 are generally rare. But in collaboration with Martin Hibberd and Michael Levin at Imperial College in London, Beutler scanned the gene for mutations in individuals with meningococcal sepsis.
Meningococcal sepsis is a rare but potentially fatal type of Gram-negative infection. (In the US alone, about 200,000 severe Gram-negative infections occur each year.)
Compared to only 3 mutations in the normal population, people susceptible to meningococcal sepsis have 14 mutations scattered across the gene, Beutler reports. In the TLR2 gene, normal individuals carry only a single mutation; among individuals with meningococcal sepsis, that "normal" mutation is extremely rare. It may be that this gene, directly or indirectly, protects against the infection.
It may prove effective to use TLR agonists based on non-toxic LPS molecules to block its onset, Beutler suggests.
"Other genes surely mediate innate immunity defense as well," Beutler added. In the distant future, he says, scientists may identify an entire collection of genes that make people particularly sensitive to infection. Beutler and his team are now screening mice for other mutations that enhance or inhibit infection.
"To solve a complex problem, always start with a strong phenodeviant," he said. "A good mutation is worth a billion transfection assays, or a million gene chips." |
