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Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene
1Howard Hughes Medical Institute and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235-9050, USA.
Abstract:
Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lpsd allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.
Insights
Mutations in the Toll-like receptor 4 (Tlr4) gene impair lipopolysaccharide (LPS) signaling. This genetic change makes mice resistant to endotoxin but vulnerable to Gram-negative infections, highlighting Tlr4
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Lipopolysaccharide (LPS) is a key component of Gram-negative bacteria, triggering immune responses.
- The Toll-like receptor 4 (Tlr4) is implicated in sensing LPS and initiating downstream signaling.
- Specific mouse strains, C3H/HeJ and C57BL/10ScCr, exhibit distinct responses to LPS.
Purpose of the Study:
- To investigate the genetic basis of altered LPS signal transduction in C3H/HeJ and C57BL/10ScCr mice.
- To elucidate the role of the Toll-like receptor 4 (Tlr4) gene in endotoxin sensitivity and Gram-negative infection susceptibility.
Main Methods:
- Genetic analysis of the Lps gene in C3H/HeJ mice.
- Sequencing of the Toll-like receptor-4 (Tlr4) gene in both mouse strains.
- Phenotypic characterization of endotoxin resistance and infection susceptibility.
Main Results:
- The Lpsd allele in C3H/HeJ mice was identified as a missense mutation in the Tlr4 gene (Pro712His).
- C57BL/10ScCr mice possess a null mutation in the Tlr4 gene.
- Both mutations disrupt LPS signal transduction, leading to endotoxin resistance.
Conclusions:
- The mammalian Tlr4 protein is crucial for recognizing lipopolysaccharide (LPS) and transducing its signal.
- Disruptions in Tlr4 function predispose to Gram-negative sepsis while largely preserving other immune functions.
- Tlr4 is a primary mediator of the host response to LPS.