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Recently, we demonstrated that a surprisingly large fraction of<jats:italic>Neisseria meningitidis<\/jats:italic>disease isolates are lipid A mutants, due to inactivating mutations in the<jats:italic>lpxL1<\/jats:italic>gene. The<jats:italic>lpxL1<\/jats:italic>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<jats:italic>lpxL1<\/jats:italic>mutant bacteria much better than human TLR4. We show that an<jats:italic>lpxL2<\/jats:italic>mutant, another lipid A mutant lacking an acyl chain at a different position, activates murine TLR4 less efficiently than the<jats:italic>lpxL1<\/jats:italic>mutant. Therefore, the<jats:italic>lpxL2<\/jats:italic>mutant in mice might be a better model for infections with<jats:italic>lpxL1<\/jats:italic>mutants in humans. Interestingly, we found that the<jats:italic>lpxL2<\/jats:italic>mutant is more virulent in mice than the wild-type strain, whereas the<jats:italic>lpxL1<\/jats:italic>mutant is actually much less virulent than the wild-type strain. These results demonstrate the crucial role of<jats:italic>N. meningitidis<\/jats:italic>lipid A structure in virulence.<\/jats:p>","DOI":"10.1128\/iai.01311-09","type":"journal-article","created":{"date-parts":[[2010,5,4]],"date-time":"2010-05-04T01:09:48Z","timestamp":1272935388000},"page":"3177-3186","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["The Structure of<i>Neisseria meningitidis<\/i>Lipid A Determines Outcome in Experimental Meningococcal Disease"],"prefix":"10.1128","volume":"78","author":[{"given":"Floris","family":"Fransen","sequence":"first","affiliation":[{"name":"Laboratory of Vaccine Research, Netherlands Vaccine Institute, Bilthoven, Netherlands"},{"name":"Department of Immunology and Infectious Diseases, Utrecht University, Utrecht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik Jan","family":"Hamstra","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Research, Netherlands Vaccine Institute, Bilthoven, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire J.","family":"Boog","sequence":"additional","affiliation":[{"name":"Laboratory of Vaccine Research, Netherlands Vaccine Institute, Bilthoven, Netherlands"},{"name":"Department of Immunology and Infectious Diseases, Utrecht University, Utrecht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos P.","family":"van Putten","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Utrecht University, Utrecht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germie P. 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