Immunity's eyes: Biologists reveal the proteins that first see dangerous microbes

Abstract

A bout 3 weeks after a 4-year-old boy visited the emergency room for a nagging eye infection-which doctors easily cured-the boy's mother arrived at the same Canadian hospital. She was infected with the same bacterium, though it had done much more than redden her eyes. She showed signs of shock: plummeting blood pressure and a racing heart. Physicians suspected the destructive overreaction of the immune system to an overwhelming bacterial infection of the blood. They gave the woman massive doses of antibiotics, but it was too late. Just hours after arriving at the hospital, she died. Both mother and son had been infected with Neisseria meningitides. Why had the boy beat the bacterium but his mother had succumbed? No one knows for sure, but the answer lie in the two having had differences in certain proteins that stud the surfaces of white blood cells. so-called toll-like receptors, or TLRs, are the key sensors guiding the body's initial reaction to bacteria, viruses, or fungi. Scientists call this first line of defense the innate immune response. Over the past 4 years, scientists have found that TLRs respond to microbial features such as a bacterium's cell wall, tail, or even its DNA. In doing the receptors trigger white blood cells to engulf and kill infectious microbes or to signal other immune cells to rally to the cause. Toll-like receptors are the eyes of the innate immune system, according to Bruce Beutler of the Scripps Research Institute in La Jolla, Calif. These receptors are the main way that the innate immune system sees pathogens. That had been a big mystery for the last 100 years or so, he says. recent discovery of the human versions of these immune sensors has ignited a research frenzy. The number of papers that have been published on toll-like receptors in the last 2 years is astounding. It's hard to keep up, says Steven R. Kleeberger of Johns Hopkins University School of Public Health in Baltimore. Insights from TLRs help immunologists fight sepsis or design vaccines that ward off infections in the first place. Someday, profiling a person's TLR genes could tell who's at risk to get sepsis, suggests Beutler. Moreover, drugs that block TLRs may stop the immune overreaction responsible for sepsis or thwart other disorders of the immune system. field is moving at the speed of light, says Fabio Re of Dana-Farber Cancer Institute in Boston. To scientists' surprise, they have even found that TLRs show up on fat cells (see box, page 153), may play a role in premature births, and may contribute to lung damage from air pollution.