LA JOLLA, CALIF—Genetic mutations may leave some people at increased risk for meningococcal sepsis. Recently, it has been proposed that rare, heterozygous missense mutations of the Toll-like receptor 4 (TLR4) gene impair the immune system’s ability to identify gram-negative bacteria, such as Neisseria meningitidis.[1]

Research conducted by Bruce Beutler, MD, and colleagues indicates that the TLR4 mutations render the immune system unable to detect the lipopolysaccharides (LPS) associated with gram-negative bacteria. When these endotoxins are not recognized, the bacteria can multiply and spread unchecked throughout the entire body. It is not known how endotoxin detection is stymied for any single mutation, but it is known that the mutations impair TLR4 function. “We believe that LPS interact with TLR4 to elicit a signal, and some mutations may prevent the protein from reaching its [target on the cell membrane], diminish the affinity of interaction, or prevent the steric change that normally follows interaction,” suggested Dr. Beutler, who is a Professor of Immunology at the Scripps Research Institute. According to Dr. Beutler, another possibility concerns cytoplasmic domain mutations, which “might prevent interaction with adapter proteins that normally propagate the signal within the cell.”

WHO IS AT RISK FOR HAVING THE MUTATIONS?

Dr. Beutler’s study included 220 genetic samples from white meningitis patients and 383 samples from healthy controls. The prevalence of TLR4B, a common mutation in white persons, was similar in the two groups. But there was a marked difference in the prevalence of the rare TLR4 mutations. In the meningitis group, 14 such mutations were found, compared with only one among controls.

The study was conducted exclusively in white people due to their low genetic diversity, Dr. Beutler explained, but he believes that the results could apply to all races. To a first approximation, said Dr. Beutler, the results suggest that about 7.5% of meningococcal sepsis cases in white patients could be due to TLR4 mutations.

Although there is no known risk profile for having the mutations, Dr. Beutler speculated that “all people are at roughly equal risk of being carriers.” His rationale is as follows: “The mutations are purely deleterious … they are not balanced polymorphisms in which heterozygotes have greater fitness.” It is likely, he added, that “these mutations have occurred recently and have not been removed by selection yet.” Therefore, it seems that there is no single group or individual with an increased risk of possessing the mutations. What is known for sure is that the mutations occurred with greater frequency in the patients with gram-negative sepsis.

Vaccination could be an option for those having the missense mutations if they could be identified and if vaccination were shown to be cost-effective. Unfortunately, mass vaccination against meningitis in the United States would be difficult because of cost. There is no gene therapy currently available to prevent or treat meningitis. However, Dr. Beutler believes that “in understanding the signaling pathway by which we detect infections of all kinds, we may move closer to the day when [gene therapy] might be a viable approach.”

—Tamara Gibb

Reference
1. Smirnova I, Mann N, Dols A, et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A. 2003;100: 6075-6080.

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