LPS sensitivity in recombinant mice lacking functional alleles at MHCII, Lps and Nramp1 genes

The Lps gene ( Tlr4) regulates murine responsiveness to bacterial lipopolysaccharide (LPS). This study was designed to test the hypothesis that other genes which control macrophage responsiveness also influence host susceptibility to LPS. We developed a group of recombinant mice to study the link among three genes in the regulation of host sensitivity to LPS and other immune responses; MHCII, Lps, and Nramp1. C2D (MHCII —/ — , Lps n/n , Nramp1 s/s ) mice were crossed with either C57BL10/ScN (MHCII +/+ , Lps d/d , Nramp1 s/s ) or C3H/HeJ (MHCII +/+ , Lps d/d , Nramp1 r/r ) to produce recombinants which are MHCII —/— , Lps d/d , and Nramp1 s/s on two different mouse backgrounds. Here we describe the development and screening of these mice. In addition, we found that the absence of a functional MHCII complex did not significantly impact sensitivity of mice to LPS in a TNFsensitization model. However, mice that carried the Nramp1 s/s genotype were more sensitive to LPS-induced sepsis.