The Structure of Neisseria meningitidis Lipid A Determines Outcome in Experimental Meningococcal Disease
ABSTRACTLipopolysaccharide (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 ofNeisseria meningitidisdisease isolates are lipid A mutants, due to inactivating mutations in thelpxL1gene. ThelpxL1mutants 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 recognizeslpxL1mutant bacteria much better than human TLR4. We show that anlpxL2mutant, another lipid A mutant lacking an acyl chain at a different position, activates murine TLR4 less efficiently than thelpxL1mutant. Therefore, thelpxL2mutant in mice might be a better model for infections withlpxL1mutants in humans. Interestingly, we found that thelpxL2mutant is more virulent in mice than the wild-type strain, whereas thelpxL1mutant is actually much less virulent than the wild-type strain. These results demonstrate the crucial role ofN. meningitidislipid A structure in virulence.