Association of chronic meningococcemia with infection by meningococci with underacylated lipopolysaccharide

Brouwer, Matthijs C.; Spanjaard, Lodewijk; Prins, Jan M.; Ley, Peter van der; Beek, Diederik van de; Ende, Arie van der

doi:10.1016/j.jinf.2011.03.010

Cited by 21 publications

(18 citation statements)

References 20 publications

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“…However, the data we have presented suggest that variations in lipooligosaccharide structure may play an important role in this phenomenon. The role of lipid A hexa-acylation directed by msbB in human disease is of particular interest given the identification of mutations in this gene in another pathogenic Neisseria species, which are associated with milder disease presentation (12,13). Though mutations that eliminate a functional lpxL1 gene (the homolog of N. gonorrhoeae msbB) in N. meningitidis have been identified in clinical isolates, these have yet to be identified in N. gonorrhoeae isolates.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with these strains had a significantly reduced severity of thrombocytopenia and petechial rash and a nonsignificant reduction in hypotension and septic shock, suggestive of reduced virulence in human infection as well (12). Further, N. meningitidis strains carrying lpxL1 mutations make up the majority of strains isolated from patients with chronic meningococcemia, which presents with a prolonged dis-ease course that lacks the symptoms of severe septic shock-associated acute meningococcal infections (13).…”

Section: Ipopolysaccharide (Lps) Is An Importance Virulence Factor Inmentioning

confidence: 99%

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Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

et al. 2014

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e Neisseria gonorrhoeae causes gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients with N. gonorrhoeae remain asymptomatic, without evidence of localized inflammation. Inflammatory responses to N. gonorrhoeae are generated by host innate immune recognition of N. gonorrhoeae by several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1␤ (IL-1␤) processing complex known as the inflammasome. The lipooligosaccharide of N. gonorrhoeae has a hexa-acylated lipid A. N. gonorrhoeae strains that carry an inactivated msbB (also known as lpxL1) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show that msbB-deficient N. gonorrhoeae induces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affect N. gonorrhoeae-mediated activation of the inflammasome. We demonstrate that N. gonorrhoeae msbB is dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection with msbB-deficient N. gonorrhoeae is associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition of N. gonorrhoeae LOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections. L ipopolysaccharide (LPS) is an importance virulence factor in Gram-negative bacteria. LPS consists of a complex polysaccharide attached to a core saccharide consisting of 3-deoxy-Dmannooctulosonic acid (keto-deoxyoctulosonate [KDO]) and an acylated diglucosamine moiety known as lipid A. Neisseria species (as well as some other commensal and pathogenic bacteria) make LPS with a truncated polysaccharide structure, which is termed lipooligosaccharide (LOS). LOS is a potent mediator of inflammatory signaling and is known to activate several host innate immune signaling systems, including toll-like receptor 4 (TLR4) through the lipid A molecule, C-lectin receptors (particularly MGL and DC-SIGN) through the oligosaccharide structure, and the caspase-1 activating complex known as the NLRP3-inflammasome through mechanisms yet to be determined (1-4).Lipid A synthesis is largely carried out by a highly conserved set of enzymatic steps that include the acylation of glucosaminebased precursors followed by condensation of these acylated glucosamine structures into the tetra-acylated disaccharide backbone that is the core structure of lipid A. This core is further decorated by the addition of two KDOs (2) and a variety of other additional modifications of the lipidated dis...

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Section: Discussionmentioning

confidence: 99%

Section: Ipopolysaccharide (Lps) Is An Importance Virulence Factor Inmentioning

confidence: 99%

Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

et al. 2014

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“…Supporting this concept, genome-wide expression profiling revealed that pathogenic N. meningitidis can suppress host responses (45). Significant evidence indicates that expression of highly phosphorylated, hexaacylated LOS that leads to homeostatic signaling in response to inflammation mediated by NF-B induction by the TIR domain-containing adaptor inducing IFN-␤ (TRIF)/TRIF-related adaptor molecule (TRAM) pathway is critical to the ability of N. meningitidis to induce immune tolerance, evade the host immune system, and cause disease (27,46,47). Importantly, the immune responses in the systemic circulation and the brain have been shown to differ as injection of LOS from N. meningitidis systemically was reported to induce tolerance, whereas injection of the LOS in the subarachnoid space of rabbits did not (46).…”

Section: Table 4 Expression Of Pea (A) O-acetate (B) and Sialic Acimentioning

confidence: 99%

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

John

Phillips²,

Din

et al. 2016

Journal of Biological Chemistry

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The degree of phosphorylation and phosphoethanolaminylation of lipid A on neisserial lipooligosaccharide (LOS), a major cell-surface antigen, can be correlated with inflammatory potential and the ability to induce immune tolerance in vitro. On the oligosaccharide of the LOS, the presence of phosphoethanolamine and sialic acid substituents can be correlated with in vitro serum resistance. In this study, we analyzed the structure of the LOS from 40 invasive isolates and 25 isolates from carriers of Neisseria meningitidis without disease. Invasive strains were classified as groups 1-3 that caused meningitis, septicemia without meningitis, and septicemia with meningitis, respectively. Intact LOS was analyzed by high resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Prominent peaks for lipid A fragment ions with three phosphates and one phosphoethanolamine were detected in all LOS analyzed. LOS from groups 2 and 3 had less abundant ions for highly phosphorylated lipid A forms and induced less TNF-␣ in THP-1 monocytic cells compared with LOS from group 1. Lipid A from all invasive strains was hexaacylated, whereas lipid A of 6/25 carrier strains was pentaacylated. There were fewer O-acetyl groups and more phosphoethanolamine and sialic acid substitutions on the oligosaccharide from invasive compared with carrier isolates. Bioinformatic and genomic analysis of LOS biosynthetic genes indicated significant skewing to specific alleles, dependent on the disease outcome. Our results suggest that variable LOS structures have multifaceted effects on homeostatic innate immune responses that have critical impact on the pathophysiology of meningococcal infections.Our previous studies of neisserial lipooligosaccharide (LOS) 2 and the human innate immune system have shown that the degree of phosphorylation of the lipid A component is correlated with the potential of the LOS to induce inflammation stimulated by innate immunity as revealed by cytokine induction in human monocytes in vitro and, in general, with the severity of infections (1-3). In the LOS of Neisseria meningitidis, the modification of lipid A with phosphoethanolamine (PEA) also has been shown to inhibit the bactericidal activity of cathepsin G within neutrophil extracellular traps (4) and to increase adhesion of the bacteria to human cells (5). Expression of PEA on the oligosaccharide (OS) of meningococcal LOS (Fig. 1), particularly in the O-3 position on heptose (Hep) II, or expression of sialic acid (Neu5Ac) have been shown to inhibit activation of complement via the classical and alternative pathways (6 -9). In this study, we postulated that analysis of the structures of the LOS and the genomic diversity of genes for LOS biosynthesis would reveal differences associated with the severity of meningococcal infection and with carrier versus invasive strains of N. meningitidis.To ascertain whether such differences exist, we characterized the structures of LOS from isolates from infected patients or from carriers of N. meningitidi...

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“…A key determinant of toxicity and pathophysiology of infections with Neisseria spp. is the acylation state of lipid A [6,7]. Modification of lipid A with PEA increases resistance of N. gonorrhoeae to complement killing and increases survival of both gonococci and meningococci in vivo [8].…”

mentioning

confidence: 99%

Analysis of Bacterial Lipooligosaccharides by MALDI-TOF MS with Traveling Wave Ion Mobility

Phillips

John

Jarvis

2016

J. Am. Soc. Mass Spectrom.

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LOS MALDI IMS-MSAbstract. Lipooligosaccharides (LOS) are major microbial virulence factors displayed on the outer membrane of rough-type Gram-negative bacteria. These amphipathic glycolipids are comprised of two domains, a core oligosaccharide linked to a lipid A moiety. Isolated LOS samples are generally heterogeneous mixtures of glycoforms, with structural variability in both domains. Traditionally, the oligosaccharide and lipid A components of LOS have been analyzed separately following mild acid hydrolysis, although important acid-labile moieties can be cleaved. Recently, an improved method was introduced for analysis of intact LOS by MALDI-TOF MS using a thin layer matrix composed of 2,4,6-trihydroxyacetophenone (THAP) and nitrocellulose. In addition to molecular ions, the spectra show in-source Bprompt^fragments arising from regiospecific cleavage between the lipid A and oligosaccharide domains. Here, we demonstrate the use of traveling wave ion mobility spectrometry (TWIMS) for IMS-MS and IMS-MS/MS analyses of intact LOS from Neisseria spp. ionized by MALDI. Using IMS, the singly charged prompt fragments for the oligosaccharide and lipid A domains of LOS were readily separated into resolved ion plumes, permitting the extraction of specific subspectra, which led to increased confidence in assigning compositions and improved detection of less abundant ions. Moreover, IMS separation of precursor ions prior to collision-induced dissociation (CID) generated time-aligned, clean MS/MS spectra devoid of fragments from interfering species. Incorporating IMS into the profiling of intact LOS by MALDI-TOF MS exploits the unique domain structure of the molecule and offers a new means of extracting more detailed information from the analysis.

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Association of chronic meningococcemia with infection by meningococci with underacylated lipopolysaccharide

Cited by 21 publications

References 20 publications

Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

Lipooligosaccharide Structures of Invasive and Carrier Isolates of Neisseria meningitidis Are Correlated with Pathogenicity and Carriage

Analysis of Bacterial Lipooligosaccharides by MALDI-TOF MS with Traveling Wave Ion Mobility

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