Skip Navigation
Archive

NIAID Archive

Important note: Information on this page was accurate at the time of publication. This page is no longer being updated.
​​
NIH HHS News Release Logo

National Institute of Allergy and
Infectious Diseases (NIAID)
http://www.niaid.nih.gov

FOR IMMEDIATE RELEASE
Sunday, July 20, 2003

Media Contact:
Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov
Skip Content Marketing
  • Share this:
  • submit to facebook
  • Tweet it
  • submit to reddit
  • submit to StumbleUpon
  • submit to Google +

Single Protein is Key in Response to Bacterial, Viral Infections

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, M.D., of The Scripps Research Institute in La Jolla, CA, 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 Dr. 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.

Dr. 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, Dr. 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, Dr. 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, M.D., 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.”

###

###

References:

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.


NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health ®

back to top


Archive

NIAID Archive

Important note: Information on this page was accurate at the time of publication. This page is no longer being updated.
​​​​

Last Updated July 20, 2003