Humanized TLR4/MD-2 Mice Reveal LPS Recognition Differentially Impacts Susceptibility to Yersinia pestis and Salmonella enterica

Although lipopolysaccharide (lps) stimulation through the toll-like receptor (tlr)-4/md-2 receptor complex activates host defense against gram-negative bacterial pathogens,how species-specific differences in lps recognition impact host defense remains undefined. herein,we establish how temperature dependent shifts in the lipid a of yersinia pestis lps that differentially impact recognition by mouse versus human tlr4/md-2 dictate infection susceptibility. when grown at 37°c,y. pestis lps is hypo-acylated and less stimulatory to human compared with murine tlr4/md-2. by contrast,when grown at reduced temperatures,y. pestis lps is more acylated,and stimulates cells equally via human and mouse tlr4/md-2. to investigate how these temperature dependent shifts in lps impact infection susceptibility,transgenic mice expressing human rather than mouse tlr4/md-2 were generated. we found the increased susceptibility to y. pestis for humanized tlr4/md-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified lps. by contrast,for other gram-negative pathogens with highly acylated lipid a including salmonella enterica or escherichia coli,infection susceptibility and the response after stimulation with lps were indistinguishable between mice expressing human or mouse tlr4/md-2. thus,y. pestis exploits temperature-dependent shifts in lps acylation to selectively evade recognition by human tlr4/md-2 uncovered with humanized tlr4/md-2 transgenic mice. © 2012 hajjar et al.