Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
The prognosis for sepsis - the presence of pathogens or their toxins in blood or tissue - is dire. It can threaten many parts of the body, from bones to brains, and death due to septic shock may come in a matter of hours.
Two percent of all those admitted to the hospital suffer from sepsis, which is one of the top 10 causes of both infant and adult mortality in the U.S. In 1999, it directly inflicted more than 30,000 deaths.
When a bacterium - say the deadly Neisseria meningitides - invades a body, it gallantly invites the immune system to stage a biochemical defense. One way that the body initially responds to such an altruistic infection is to recruit white blood cells, typically macrophages, which engulf the infectious intruder and destroy it. Another arrow to the phage's quiver is depositing inflammatory chemicals at the site of an infection. But there's a limit to how much inflammation a body can take. Sepsis, also known as septic shock and systemic inflammatory response syndrome, features a state of shock to one's organs, followed by poisoning with these pathogenic endotoxins.
Meningococcal sepsis and shock, reacting to endotoxin poisoning, is a potentially fatal condition. It is just one form of Gram-negative infection. In all, about 200,000 such diseases occur in the U.S. each year. About half of those who contract meningococcal sepsis are under the age of 2, and the hospital horror has an overall case fatality rate of 12 percent.
Rare genetic mutations may heighten susceptibility to infection and death from bacterial meningitis. So reports a paper in the Proceedings of the National Academy of Sciences (PNAS), released online April 28, 2003. Its title: "Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility." Its co-authors are pediatric immunologists at the Scripps Research Institute in La Jolla, Calif.
Toll-like receptor 4, or TLR4, is that title's key term. "Toll" is a German word meaning "raving mad, frantic, crazy, wild." When scientists found an erratic gene in the fruit fly genome, they dubbed it "toll," and it stuck. "The TLRs are the eyes of the innate immune system," observed immunologist Bruce Beutler, the PNAS paper's senior author. He had suspected that those eyes may be myopic for some people, and that mutations in the TLR4 gene may underlie the genetic component of severe sepsis.
To confront this hunch, Beutler looked for extremely rare mutations in the human genome, by obtaining hundreds of DNA samples from his British co-author, Martin Hibberd. He then amplified and sequenced the entire TLR4 gene from each sepsis patient, looking for all the seldom-seen mutations present in the gene. That departed from the traditional approach of seeking one common mutation within one gene. He found a significant excess of low-frequency mutations in the TLR4 genes of patients who had contracted sepsis vs. the ethnically and geographically matched control cohort. Instead of asking how many subjects packed one single mutation, the Scripps team simply sought how many had any genetic variation at all.
"This is the first time," Beutler said, "that a comparison of the collective mutations at a given genetic locus has been made in any infectious disease. Our technique of measuring the genetic-variation load' of the entire gene locus could be applied to other sorts of diseases as well, particularly those in which both genes and environment play a role.
"Besides demonstrating that the risk of severe sepsis increases with these mutations, which can be passed from parent to child," Beutler continued, "our study also suggests that it may be possible to protect people who are at risk. While not practical at the moment," he allowed, "eventually patients with mutations in their TLR4 genes might be given prophylactic treatment. For instance, before they undergo surgery or travel somewhere, they are likely to be exposed to meningococcal bacteria."
Beutler made the point that "certain strains of mice are more susceptible to infection with bacteria like N. meningitides - but nobody had ever shown this to be true in humans. Now, we have found a number of rare mutations in one essential gene of the innate immune system - the Toll-like receptor, which is important in endotoxin recognition, giving people a higher probability of contracting meningococcal sepsis. In the future, genetic analysis may indicate which individuals are most likely to develop meningitis," he concluded, "and could therefore benefit from treatment."
Time In Womb Declines When Famished Ewe Conceives; Risk Imperils Human Moms, Too
Female sheep that were undernourished around the time of conception carried their unborn lambs for a shorter time than their fully fed peers, according to a new study that may help doctors understand human preterm pregnancies. The paper appears in Science dated April 25, 2003, under the title "A periconceptional nutritional origin for nonifectious preterm birth." Its authors are in Canada, Australia and New Zealand.
Preterm births are a significant health problem, they note. Their frequency is on the rise, and the cause of 60 percent of these abbreviated human pregnancies remains unknown. The authors decreased the food ration for a group of sheep 60 days before conception and maintained this reduced diet for the first 30 days of the pregnancy. Lambs from undernourished mothers were born significantly earlier than offspring from dams on full feed. Fetal hormone levels, critical to a final stage of maturation, and necessary for birthing process, followed markedly different patterns based on the nutrition of the mother at conception.
"There could be down-the-road implications for what prospective moms should be eating, if these findings are applicable to human pregnancy," observed the article's first author. He explained that preterm babies born after fewer than 30 weeks in the womb are at major risk for cerebral palsy and learning difficulties.