title: The structure of Neisseria meningitidis lipid A determines outcome in experimental meningococcal disease.
abstract: Lipopolysaccharide (LPS), a major component of the meningococcal outer membrane, is sensed by the host through activation of Toll-like receptor 4 (TLR4). Recently, we demonstrated that a surprisingly large fraction of Neisseria meningitidis disease isolates are lipid A mutants, due to inactivating mutations in the lpxL1 gene. The lpxL1 mutants activate human TLR4 much less efficiently than wild-type bacteria, which may be advantageous by allowing them to escape from the innate immune system. Here we investigated the influence of lipid A structure on virulence in a mouse model of meningococcal sepsis. One limitation, however, is that murine TLR4 recognizes lpxL1 mutant bacteria much better than human TLR4. We show that an lpxL2 mutant, another lipid A mutant lacking an acyl chain at a different position, activates murine TLR4 less efficiently than the lpxL1 mutant. Therefore, the lpxL2 mutant in mice might be a better model for infections with lpxL1 mutants in humans. Interestingly, we found that the lpxL2 mutant is more virulent in mice than the wild-type strain, whereas the lpxL1 mutant is actually much less virulent than the wild-type strain. These results demonstrate the crucial role of N. meningitidis lipid A structure in virulence.
authors.affiliation: Laboratory of Vaccine Research, Netherlands Vaccine Institute, Bilthoven, Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: Fransen
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Hamstra
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Boog
authors.forename: Jos P
authors.initials: JP
authors.lastname: van Putten
authors.forename: Germie P J M
authors.initials: GP
authors.lastname: van den Dobbelsteen
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology; D008050:Lipid A / Q000276:immunology / Q000502:physiology*; D008589:Meningococcal Infections / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009345:Neisseria meningitidis / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000502:physiology
chemical_list: D001425:Bacterial Outer Membrane Proteins; D016207:Cytokines; D008050:Lipid A; D051197:Toll-Like Receptor 4