Lipooligosaccharide structure contributes to multiple steps in the virulence of Neisseria meningitidis.
Lipooligosaccharide (LOS) of Neisseria meningitidis has been implicated in meningococcal interaction with host epithelial cells and is a major factor contributing to the human proinflammatory response to meningococci. LOS mutants of the encapsulated N. meningitidis serogroup B strain NMB were used to further determine the importance of the LOS structure in in vitro adherence and invasion of human pharyngeal epithelial cells by meningococci and to study pathogenicity in a mouse (CD46 transgenic) model of meningococcal disease. The wild-type strain [NeuNAc-Galbeta-GlcNAc-Galbeta-Glcbeta-Hep2 (GlcNAc, Glcalpha) 3-deoxy-D-manno-2-octulosonic acid (KDO2)-lipid A; 1,4' bisphosphorylated], although poorly adherent, rapidly invaded an epithelial cell layer in vitro, survived and multiplied early in blood, reached the cerebrospinal fluid, and caused lethal disease in the mouse model. In contrast, the Hep2 (GlcNAc) KDO2-lipid A (pgm) mutant, which was highly adherent to cultured epithelial cells, caused significantly less bacteremia and mortality in the mouse model. The Hep2-KDO2-lipid A (rfaK) mutant was shown to be moderately adherent and to cause levels of bacteremia and mortality similar to those caused by the wild-type strain in the mouse model. The KDO2-lipid A (gmhB) mutant, which lacks the heptose disaccharide in the inner core of LOS, avidly attached to epithelial cells but was otherwise avirulent. Disease development correlated with expression of specific LOS structures and was associated with lower adherence but rapid meningococcal passage to and survival in the bloodstream, induction of proinflammatory cytokines, and the crossing of the blood-brain barrier. Taken together, the results of this study further define the importance of the LOS structure as a virulence component involved in multiple steps in the pathogenesis of N. meningitidis.
Plant
Laura
L
Department of Medical Biochemistry and Microbiology, Biomedical Centrum, Uppsala University, PO Box 582, Uppsala, Sweden. Laura.Plant@imbim.uu.se
Sundqvist
Johanna
J
Zughaier
Susu
S
Lövkvist
Lena
L
Stephens
David S
DS
Jonsson
Ann-Beth
AB
D000818:Animals; D001422:Bacterial Adhesion; D001769:Blood / Q000382:microbiology; D001812:Blood-Brain Barrier / Q000382:microbiology; D002240:Carbohydrate Sequence; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D008589:Meningococcal Infections / Q000382:microbiology / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D038541:Neisseria meningitidis, Serogroup B / Q000235:genetics / Q000472:pathogenicity*; D010614:Pharynx / Q000166:cytology / Q000382:microbiology
D016207:Cytokines; D008070:Lipopolysaccharides; D051916:Membrane Cofactor Protein; C023023:lipid-linked oligosaccharides