Non-lipooligosaccharide-mediated signalling via Toll-like receptor 4 causes fatal meningococcal sepsis in a mouse model.
Meningococcal lipooligosaccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis with disease severity correlating with circulating concentrations of LOS and proinflammatory cytokines. In this study we show that the proinflammatory response to live meningococci in a mouse model of sepsis involves TLR4, but can develop independently of the expression of LOS. This is supported by data showing that in vivo an isogenic LOS-deficient strain, lpxA, induced equivalent disease severity and similar proinflammatory responses as the serogroup C wild-type parent strain FAM20. This response was abolished in TLR4-/- mice, and neither the wild-type strain of meningococci nor the LOS-deficient mutant was able to cause fatal sepsis in these mice. Mouse survival correlated with low levels of cytokines and chemokines, the chemotactic complement factor C5a and neutrophil levels in blood at 24 h post infection. These data suggest that during meningococcal sepsis the recognition of one or more unidentified non-LOS component(s) by TLR4 is important in stimulating proinflammatory responses, and that fatality associated with meningococcal sepsis in mice is induced by the proinflammatory host response.
Plant
Laura
L
Smittskyddsinstitutet, Swedish Institute for Infectious Disease Control, Karolinska Institutet, Nobelsväg 18, 171 77 Solna, Sweden. Laura.Plant@smi.ki.se
Wan
Hong
H
Jonsson
Ann-Beth
AB
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D008589:Meningococcal Infections / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D015398:Signal Transduction / Q000502:physiology*; D015996:Survival Rate; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C023023:lipid-linked oligosaccharides