The findings, which appear in the April 28 online issue of the Proceedings of the National Academy of Sciences, may help prevent the disease in people who have one or more of the mutations and are at high risk.
The study gives more details of an increasingly complex picture. "This is just a piece of the pie. This is not the whole thing," says Dr. Rodrigo Hasbun, an associate professor of medicine at Tulane University School of Medicine in New Orleans.
Meningitis is an inflammation of the lining of the brain and the spinal cord. Most commonly, it is caused by a bacteria or virus. Bacterial meningitis is the more serious form of the disease and is usually caused by the meningococcal or the pneumococcal bacteria. This study looked at the meningococcal form of the disease.
In extreme cases, the infection can progress to sepsis, which means it spreads to many parts of the body and can cause death or life-long debilitation. Meningococcal sepsis affects more than 2,500 people a year in the United States, about half of whom are under the age of 2. Some 12 percent of those who contract the disease die of it.
While many individuals harbor the bacteria that causes meningitis in their nose, throat and upper respiratory tract, only a tiny proportion actually develop the disease.
Scientists have already recognized certain factors that affect susceptibility to the disease.
"The first thing that has been well known for several years is complement deficiency," Hasbun explains. "Patients that have genetically deficient complement are definitely at higher risk of having the disease."
Complements work with antibodies to kill certain types of bacteria. Without complements, antibodies simply can't do their job. There is already a test in existence to determine who has this deficiency.
The second area is "mannose-binding lectin," a protein that activates the complement to bind to the antibody. Again, when this is missing or defective, patients cannot mount an effective defense.
The current study describes a third aspect of innate immunity. Individuals who have their spleen taken out are also at risk, but that is considered acquired immunity.
The authors of the paper analyzed genetic information from more than 200 English, Dutch and American children with meningococcal disease. Then, using a special software designed just for this purpose, they sequenced the entire TLR4 (toll-like receptor 4) gene from each patient, looking for aberrations.
There were clear points of difference in the TLR4 genes of the people who had contracted sepsis compared to healthy controls. The TLR4 gene "normally detects endotoxin, an essential structural component of gram-negative bacteria [like the meningococcus]," explains Dr. Bruce Beutler, senior author of the paper and a professor of immunology at the Scripps Research Institute in La Jolla, Calif. "Without it, the body does not recognize that there is an infection at an early stage, and cannot overcome it."
When bacteria infect the body, they trigger the immune system to recruit white blood cells to fight the pathogens by producing inflammation. If the infection is particularly widespread, the endotoxin levels might be so high that they produce a lethal level of inflammation. This can result in sepsis.
Individuals with TLR4 mutations can no longer detect the presence of gram-negative bacteria. "When they can't sense that type of bacteria in the bloodstream, it's not going to be able to send its soldiers to fight it," Hasbun says.
"This is the first time that mutations in any of the toll-like receptors (of which there are ten in humans) have been clearly implicated in a disease," Beutler says.
Broad-spectrum antibiotics are usually used to fight bacterial meningitis but may not be effective if the infection is too severe or widespread. A meningococcal vaccine does exist, but it's not feasible to administer it to everyone, given the small number of people who contract the disease. A test for complement deficiencies can identify some people who should get a vaccine. The current findings may pave the way for another test.
"Hopefully, the benefit will be a nice, easy, not costly test that we could use to try to identify who's at risk for having this type of infection so we can vaccinate those patients," Hasbun says. "Currently it's not cost-effective to vaccinate everybody because the incidence is so low, but if we could identify who's at risk, we could just vaccinate them."
"Some day, as sequencing technology advances, it might be feasible to determine the genotype of individuals at all of the toll-like receptor loci (including TLR4) and at other loci that might produce susceptibility to infection," Beutler adds. "One could then try to protect people who are at risk through a program of vaccination or antibiotic treatment before a serious infection has a chance to start."