Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in <i>Tlr4</i> Gene

TLDR

Mutations in the Lps gene disrupt LPS signaling in C3H/HeJ and C57BL/10ScCr mice, rendering them endotoxin‑resistant yet highly susceptible to Gram‑negative infections. The Lps d allele is a missense mutation (P712H) in Tlr4, and a null Tlr4 allele in C57BL/10ScCr, showing that loss of Tlr4 function confers endotoxin resistance and heightened Gram‑negative sepsis risk while preserving other immune functions.

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 Lps d 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.