LA JOLLA, CALIF—Using a technique referred to as “forward genetics,” scientists recently found that the so-called Trif protein is crucial to the development of inflammation and other immune responses to bacterial and viral infection in mice and probably plays a similar role in humans.[1] The existence of Trif has been known for several months, but until now the protein’s purpose has been unclear.

If Trif is shown to have the same effect in humans as it does in mice, there could eventually be major treatment implications, said principal investigator Bruce Beutler, MD. “Blocking this pathway might have a positive effect in some sepsis cases,” speculated Dr. Beutler, who is a Professor of Immunology at the Scripps Research Institute in La Jolla, California.

A SIMPLE TECHNIQUE

The forward genetics technique that was so pivotal to Dr. Beutler’s research is relatively simple: Mice are given a chemical mutagen and then screened for immune system defects. The appearance of a defect makes it possible to locate the mutated gene responsible for it and to determine the normal gene’s function.

“After screening several thousand mice, we found one that did not make tumor necrosis factor in response to the bacterial cell wall component endotoxin, or lipopolysaccharide,” Dr. Beutler related. Because different toll-like receptors are involved in the immune response to viruses and gram-negative bacteria (TLR3 and TLR4, respectively), he and his team also tested the mouse with the mutated gene using double-stranded RNA, which is a viral product. Again, they found that no tumor necrosis factor was released.

These findings suggest that the two TLRs share an adapter protein that is responsible for transducing the warning signals they produce following bacterial or viral invasion. Dr. Beutler and colleagues found the shared protein, Trif, on a miniscule segment of chromosome 17 in the mouse with the mutated gene.

PREVIOUS SUSPICIONS WERE WRONG

Before this study, it had been suspected that Trif might be an adapter protein for TLR3 or for all of the TLRs. “We showed that it was actually specific for TLR3 and TLR4,” Dr. Beutler pointed out. Thus, in normal mice, Trif transduces signals from both viruses and gram-negative bacteria—the first adapter protein known to do so. He added that the fact that TLR3 and TLR4 share Trif helps to explain why severe viral and gram-negative infections can be so similar symptomatically, even though viruses and bacteria are completely different from one another structurally.

—Timothy Begany

Reference
1. Hoebe K, Du X, Georgel P, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature. 2003;424:743-748.

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