Inherited Susceptibility to Meningococcal Disease

Release Date:
4/16/2004
Contact:
Kirstie Saltsman
saltsmank@nigms.nih.gov

Meningococcal disease is a potentially fatal illness caused by the bacterium Neisseria meningitides. This bacterium is commonly found in the noses and throats of healthy people, but occasionally it invades the fluid surrounding the brain and spinal cord and causes meningitis. Worse still, the bacterium may seep into the bloodstream, causing meningococcal sepsis, an overwhelming, generalized blood infection. Neither scenario is good news: 2 percent of those who develop meningitis die from the infection, while the fatality rate for those who come down meningococcal sepsis is 12 percent. Roughly 2,400 cases of meningococcal disease occur in the United States annually, and most of its victims are infants or young adults 1. Given that Neisseria meningitides is harmless to most of us, scientists have long suspected that a person's genes play a role in determining whether or not meningococcal disease will develop.

Bruce Beutler, M.D., an immunologist at The Scripps Research Institute, has been studying a family of genes that is involved in "innate" immunity, the body's initial, broad defense response to invading microbes. These genes, called the Toll-like receptors (TLRs), were discovered in fruit flies, and it was in this insect model system that were first found to be involved in providing immunity.

One TLR Beutler has taken a particular interest in, toll-like receptor 4 (TLR4), binds to a molecule on the exterior surface of Neisseria meningitides bacteria. TLR4 sounds an early alarm when the bacteria breach our barriers, summoning immune cells to destroy the invaders. A defect in TLR4 could potentially allow the bacteria to get a toe-hold and lead to an overwhelming infection.

By comparing the DNA sequences of 220 people who had meningococcal disease with the sequences of 283 healthy control subjects, and using special software he designed, Beutler identified a number of rare variations in TLR4 that correlated with susceptibility to the disease. His results suggest that these variant sequences predispose a person to meningococcal disease by impairing the ability to respond in the first minutes or hours of a bacterial invasion.

In addition to providing evidence for a genetic basis to meningitis susceptibility, Beutler findings pave the way for the development of diagnostic tests for those at risk. In the future, preventive treatment could be given to those with risk-increasing TLR4 mutations prior to surgery or travel to areas where meningococcal disease epidemics are in progress. In addition, the approach that Beutler has pioneered may be applied to the study of other diseases in which both genes and environment play a role.