Lps2 and signal transduction in sepsis: At the intersection of host responses to bacteria and viruses

Bruce Beutler, Kasper Hoebe, Xin Du, Edith Janssen, Philippe Georgel, Koichi Tabeta

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4. The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized. Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease. As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs. Random germline mutagenesis identified a locus, Lps2, which is required for normal responses to double-stranded RNA and LPS. Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways. The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus. Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection. It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases. Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation. This adapter is responsible for shared effects of responses to viral and bacterial pathogens.

Original languageEnglish (US)
Pages (from-to)563-567
Number of pages5
JournalScandinavian Journal of Infectious Diseases
Volume35
Issue number9
DOIs
StatePublished - Nov 10 2003

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Microbiology (medical)
  • Infectious Diseases

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