Proinflammatory Responses to Lipo‐oligosaccharide of<i>Neisseria meningitidis</i>Immunotype Strains in Relation to Virulence and Disease

Braun, Jan-Matthias; Blackwell, C. Caroline; Poxton, Ian R.; Ahmer, Omar El; Gordon, Ann E.; Madani, Osama M. Al; Weir, D. M.; Giersen, Sonja; Beuth, Josef

doi:10.1086/340501

Cited by 26 publications

(31 citation statements)

References 45 publications

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“…Our previous work and that of others has shown that the LA portion of Neisserial LOS is the bioactive component (6,(10)(11)(12)(13). Several studies have shown with the use of mutational or enzymatic alterations of LOS that structural modifications of Neisserial LA result in substantial differences in biological potency (11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 94%

“…There have been several reported mutational or enzymatic alterations of the acylation pattern of the Neisserial LA leading to modulation of its endotoxic activity as measured by various assays (11)(12)(13). Inactivation of genes lpxL1 or lpxL2 involved in acylation of the LA resulted in a lipid, which was pentaacylated or tetraacylated, respectively, rather than hexaacylated, and in both cases the LOS induced less TNF-a from a human macrophage cell line (13).…”

mentioning

confidence: 99%

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Profiles of structural heterogeneity in native lipooligosaccharides of Neisseria and cytokine induction

John

Liu

Jarvis

2009

Journal of Lipid Research

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Fine differences in the phosphorylation and acylation of lipooligosaccharide (LOS) from Neisseria species are thought to profoundly influence the virulence of the organisms and the innate immune responses of the host, such as signaling through toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells (TREM). MALDI time-of-flight (TOF) mass spectrometry was used to characterize heterogeneity in the native LOS from Neisseria gonorrheae and N. meningitidis. A sample preparation methodology previously reported for Escherichia coli lipopolysaccharide (LPS) employing deposition of untreated LOS on a thin layer of a film composed of 2,4,6-trihydroxyacetophenone and nitrocellulose was used. Prominent peaks were observed corresponding to molecular ions and to fragment ions primarily formed by cleavage between the 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) and the lipid A (LA). Analyses of these data and comparison with spectra of the corresponding Odeacylated or hydrogen fluoride-treated LOS enabled the detection of novel species that apparently differed by the expression of up to three phosphates with one or more phosphoethanolamine (PEA) groups on the LA. We found that the heterogeneity profile of acylation and phosphorylation correlates with the induction of proinflammatory cytokines in THP-1 monocytic cells. This methodology enabled us to rapidly profile components of structural variants of native LOS that are of importance biologically.-John, C. M., M. Liu, and G. A. Jarvis. Profiles of structural heterogeneity in native lipooligosaccharides of Neisseria and cytokine induction. J. Lipid Res. 2009. 50: 424-438. Supplementary key words lipooligosaccharideThe lipooligosaccharide (LOS) of Neisseria gonorrheae and N. meningitidis is structurally related to the lipopolysaccharide (LPS) of enteric Gram-negative bacteria but does not have repeating O-antigens (1). LOS and LPS have conserved inner cores composed of L-glycero-D-manno-heptose (Hep) and 3-deoxy-D -manno-oct-2-ulosonic acid (Kdo), which are anchored in the outer membrane by lipid A (LA). The structure of the LA of gonococci and meningococci, although based on a limited number of studies, generally differs from that of Escherichia coli in the acylation and the chain length of the fatty acid residues. With regard to phosphorylation, a limited number of studies have shown that gonococci and meningococci elaborate LOS containing a LA, which is phosphorylated with variable numbers of phosphate (P) and phosphoethanolamine (PEA) residues. The recent report of a PEA transferase specific for the LA on meningococcal LOS creates the possibility of phase variation in phosphorylation (2). Thus, the LA expressed by these organisms exhibit heterogeneity in acylation and phosphorylation, both of which have been shown to influence the endotoxicity in E. coli LPS (3).The innate immune response to bacterial pathogens relies on the detection of pathogen-associated molecular patterns by pattern recognition molecules. Toll-like receptor 4 (TLR4) is one of...

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Profiles of structural heterogeneity in native lipooligosaccharides of Neisseria and cytokine induction

John

Liu

Jarvis

2009

Journal of Lipid Research

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“…It is therefore likely that the variation we see in the TNF response of THP-1 cells and in TLR4/MD2 signaling induced by LOS from different Neisseria strains is due to differences in the lipid A portion of the molecule. There have been many reported alterations of lipid A structure leading to modulation of its endotoxic activity as measured by various assays (4,9,43,49). It has been shown that the acylation pattern of lipid A is an important determinant of endotoxin activity.…”

Section: Discussionmentioning

confidence: 99%

Activation of Toll-Like Receptor 2 (TLR2) and TLR4/MD2 by Neisseria Is Independent of Capsule and Lipooligosaccharide (LOS) Sialylation but Varies Widely among LOS from Different Strains

et al. 2003

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Lipooligosaccharide (LOS) structure and capsular polysaccharide of Neisseria meningitidis each greatly influence the virulence of the organism and the quality of host innate immune responses. In this study, we found that production of the proinflammatory cytokine tumor necrosis factor (TNF) by a human monocytederived cell line (THP-1) exposed to strains of N. meningitidis lacking capsule and/or with truncated LOS was similar to that elicited by the isogenic wild-type strain. These mutants also exhibited no difference in induction of the interleukin-8 (IL-8) promoter in a transfected HeLa cell system of Toll-like receptor 2 (TLR2) and TLR4/MD2 signaling. However, purified LOS from diverse strains of Neisseria (both N. meningitidis and N. gonorrhoeae) caused widely variant levels of IL-8 promoter induction in cells expressing MD2 that correlated with the production of TNF from THP-1 cells. These data suggest that although modification of the oligosaccharide chain of LOS and/or absence of capsule do not affect cell signaling mediated by TLR4/MD2, finestructural differences in the LOS do influence signaling through TLR4/MD2 and, through this pathway, influence some of the proinflammatory responses elicited by Neisseria.Neisseria meningitidis is an important cause of sepsis syndrome and meningitis, the severity of which is correlated with the release of proinflammatory cytokines (50, 51). The lipooligosaccharide (LOS) of N. meningitidis, like other gram-negative bacteria, is a potent stimulator of the proinflammatory response, and plasma LOS levels correlate with the severity of disease (3). Neisserial LOS is composed of a hydrophobic lipid A portion that anchors it to the bacterial outer membrane, and this is linked to a hydrophilic oligosaccharide core, which is exposed on the surface. However, it does not possess the repeating O-polysaccharide region that is seen in the lipopolysaccharide (LPS) of many other bacteria. The outer core of the LOS is highly variable, and this forms the basis of strain immunotyping (41). The lipid A structure of both N. meningitidis (29) and N. gonorrhoeae (44) consists of a ␤-D-glucosaminyl-(1Ј36)-D-glucosamine disaccharide backbone with variable patterns of phosphorylation and fatty acid acylation (23).Addition of sialic acid to the terminal galactose moiety of the lacto-N-neotetraose of meningococcal LOS and the polysialic acid capsule of serogroup B organisms both determine virulence through the regulation of complement (10,20,22) and also by modification of a number of innate host immune responses, including expression of phagocyte adhesion molecules (26) and nonopsonic macrophage phagocytosis of the organism (38).The Toll-like receptors (TLRs) have been shown to initiate innate proinflammatory signal transduction in response to a number of pathogen-associated molecular patterns (33,34,39). TLR4, with its cofactor MD2, has been shown to respond to LPS (30,42), and TLR2 responds to lipoproteins (2) and peptidoglycan (45). TLR3, TLR5, and TLR9 respond to double-stranded RNA (1), fla...

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“…Pre-incubation with VitD3 did not affect either the type or quantity of cytokines tested, but this step was retained in our studies. In contrast to endotoxin, 25 expression of the CD14 antigen does not appear to affect responses of THP-1 cells to A. otitidis or S. pneumoniae.…”

Section: Cytokines Stimulated By a Otitidismentioning

confidence: 78%

“…To induce expression of CD14, THP-1 cells (2.5 Â 10 5 cells/ml) were pretreated with 10 À7 M VitD3 for 72 h prior to use in stimulation assays. 25 CD14 expression of VitD3-differentiated THP-1 cells was confirmed by flow cytometry (Hunter Area Pathology Service, Newcastle, Australia).…”

Section: Materials and Reagentsmentioning

confidence: 98%

In vitro inflammatory responses elicited by isolates of Alloiococcus otitidis obtained from children with otitis media with effusion

et al. 2013

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Alloiococcus otitidis is usually detected in children with otitis media (OM) by PCR as it is not often detected by routine culture. Our improved method for its isolation obtained A. otitidis from nearly 50% of 78 children with OM with effusion. The role of A. otitidis in pathogenesis of OM is unclear. This study tested two hypothesis: (1) that fresh isolates of A. otitidis would elicit pro-inflammatory cytokines from THP-1 monocytic cells equivalent to those induced by Streptococcus pneumoniae; (2) priming THP-1 cells with interferon-gamma (IFN-γ) a surrogate for virus infection, would enhance pro-inflammatory responses. Recent clinical isolates of A. otitidis, S. pneumoniae (ATCC 49619) and a blood culture isolate of S. pneumoniae (SP2) were used in the assays. Cytokines were quantified by BioRad bead assay and Luminex 200. IFN-γ priming enhanced cytokine responses. S. pneumoniae ATCC 49619 induced lower responses than SP2 for IL-1β, IL-6, TNF-α. A. otitidis LW 27 elicited higher IL-1β and TNF-α responses than either pneumococcal isolate. Small green colony types of A. otitidis induced higher responses than large white colony types for IL-8 and IL-1β. The hypothesis that A. otitidis elicits cytokines observed in middle ear effusions was supported; the need to use recent clinical isolates in studies of pathogenesis was highlighted.

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Proinflammatory Responses to Lipo‐oligosaccharide ofNeisseria meningitidisImmunotype Strains in Relation to Virulence and Disease

Cited by 26 publications

References 45 publications

Profiles of structural heterogeneity in native lipooligosaccharides of Neisseria and cytokine induction

Profiles of structural heterogeneity in native lipooligosaccharides of Neisseria and cytokine induction

Activation of Toll-Like Receptor 2 (TLR2) and TLR4/MD2 by Neisseria Is Independent of Capsule and Lipooligosaccharide (LOS) Sialylation but Varies Widely among LOS from Different Strains

In vitro inflammatory responses elicited by isolates of Alloiococcus otitidis obtained from children with otitis media with effusion

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