Researchers recently provided important new details about the innate immune response, the first line of immunological defence against pathogens. Bruce Beutler (Scripps Research Institute, La Jolla, CA, USA) and colleagues report that the protein Trif is an adaptor for both the Tolllike receptor 3 (TLR3) and TLR4 (Nature; published online July 23; DOI 10.1038/nature01889).
Because these two receptors recognise double—stranded RNA and bacterial endotoxin, respectively, this finding explains why infectious agents as different as viruses and bacteria can produce similar symptoms, says Beutler. His results are confirmed in an independent publication from a Japanese group headed by Shizuo Akira (Osaka University, Japan; Science 2003; 301: 640–43).
Unlike the adaptive immune response in which specific antibodies and T—cell receptors are produced in response to individual pathogens, in the innate immune response germline—encoded sensors detect general features of pathogens. In 1998, Beutler identified TLR4 as the receptor for the bacterial endotoxin lipopolysaccharide (LPS), a common constituent of Gram—negative bacteria, and it is now known that ten TLRs are encoded in the human genome, which between them can probably detect every type of microbe.
To find out more about the innate immune system, Beutler's team introduced germline mutations into mice and looked for animals that were unresponsive to LPS. These mice, which were susceptible to viral infections, have a mutation in a Toll/interleukin—1 receptor/resistance adaptor protein called Trif. On the basis of this and additional findings, the researchers conclude that Trif is a key component of TLR3—mediated and TLR4—mediated signalling pathways. “Our results suggest that the LPS signalling pathway has just two branches from TLR4, one of which requires Trif”, says Beutler. “Mutations in either branch might enhance susceptibility to infection.”
“It is critically important for us to understand the innate immune response if we are to improve treatment for human sepsis”, comments Steven Opal (Brown University Medical School, Providence, RI, USA). The Trif adaptor, he suggests, could provide a target for small molecule inhibitors to block sepsis. And, say both Opal and Beutler, Trif inhibitors could also be useful when a viral infection causes overwhelming inflammation, as for example in severe acute respiratory syndrome.