Bruce Beutler

The immune system is well known for its ability to discriminate self from non-self. Innate perception of non-self depends upon receptors encoded in the germ line. My research has been directed toward the identification of these receptors and understanding their mode of action. By positional cloning, my colleagues and I discovered the principal sensors that alert the immune system to infection by gram negative bacteria. We identified Toll-like receptor 4 (TLR4) as the signaling core of the receptor for bacterial lipopolysaccharide. It proved to be a member of a family of proteins, which act in concert to detect most microbes, including bacteria, fungi, and viruses, triggering a powerful inflammatory response. Receptors of the same family also appear to mediate sterile inflammation and autoimmunity. We have used random germline mutagenesis to dissect the molecular pathways through which TLRs signal, and looking more broadly, have sought to identify all proteins with defined importance in host immune defense. This we pursue by positionally cloning chemically-induced mutations that produce immunologically abnormal phenotypes in mice. The essential proteins we have identified include sensing, signaling, effector, and homeostatic proteins (that permit us to survive our own immune response); also proteins specifically required for ontogeny of immune cells.