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 plasm a mem bra ne. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, Leaving most aspects of immune function intact.