Single Protein is Key in Response to Bacterial and Viral Infections

WASHINGTON, D.C. -- A single protein acts as a key switch point in frontline immune system reactions to both bacterial and viral infections, according to a report published online today in the journal Nature. In determining how this protein functions, a team of scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID) can now explain why certain symptoms, such as fever, occur regardless of the cause of infection.

Bruce Beutler, MD, of The Scripps Research Institute in La Jolla, Calif., who led the team, says, "This protein, Trif, stands at a crossroads in the mouse innate immune system and, by inference, we believe in the human immune system as well." A clear understanding of Trif's role in sparking inflammation gives scientists an obvious target for drugs designed to combat the runaway inflammation characteristic of many infectious and immune-mediated diseases.

Mammals, including humans, employ a family of proteins (called toll-like receptors, or TLRs) in first-line defense against bacteria and viruses. One protein, TLR-3, is activated by viruses, while another, TLR-4, responds to molecules frequently contained in bacterial cell walls. The TLRs are an important part of the innate immune system, the all-purpose "first-responder" arm of the immune system. Once activated by invading pathogens, TLRs relay the alarm to other actors in the immune system. In short order, the innate immune system responds with a surge of chemicals that together cause inflammation, fever and other responses to infection or injury.

Defining the intervening steps in the signaling pathway from TLR activation to inflammatory response is an important objective of Beutler's research. Previously, scientists had discovered a "transducer" protein responsible for passing on the news of a bacterial attack. Mice lacking this protein could still fight bacterial infection, although not very well. There had to be at least one more transducer protein.

Beutler's team found this mystery protein through a technique called "forward genetics." Genetic mutations are randomly introduced into strains of mice. A sensitive screening mechanism allows the researchers to pick out any mice that, by chance, show interesting characteristics, such as weakened responses to infection. In the latest research, Beutler and his colleagues identified a mouse whose immune system did not react to a substance called endotoxin, a component of bacterial cell walls. Subsequently, the team determined the consequence of the genetic error in these mice - they cannot produce working Trif protein.

Lack of Trif explained why the mutant mice could not respond adequately to endotoxin (which mimics bacterial infection). However, Beutler notes, the team also made the surprising observation that mice missing Trif are also unable to respond to the double-stranded RNA produced by most viruses and thus could not fight off viral infections.

The scientists inferred that both the bacteria-sensing TLR-4 pathway and the virus-sensing TLR-3 pathway are blocked when Trif is defective. This is the first innate immune system transducer protein discovered that mediates signals generated by both bacterial and viral infection.

"Scientists have been searching for the endotoxin signaling molecules of the innate immune system for more than four decades," says Daniel Rotrosen, MD, director of NIAID's Division of Allergy, Immunology and Transplantation. "We've witnessed an explosion of information on innate immunity in the past five years, catalyzed by the discovery of the TLR family of signaling molecules," he adds. "NIAID's grant to Scripps enables scientists from diverse disciplines spanning biology and informatics to tackle a wide variety of problems in innate immunity. This finding is the first of what we anticipate will be many discoveries made possible by forward genetics and other cutting-edge technologies supported through this grant."

NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference: K Hoebe et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signaling. Nature. Published online July 20, 2003. DOI: 10.1038/nature01889.