Phosphoethanolamine Substitution of Lipid A and Resistance of<i>Neisseria gonorrhoeae</i>to Cationic Antimicrobial Peptides and Complement-Mediated Killing by Normal Human Serum

Lewis, Lisa A.; Choudhury, Biswa; Balthazar, Jacqueline T.; Martin, Larry E.; Ram, Sanjay; Rice, Peter A.; Stephens, David S.; Carlson, Russell W.; Shafer, William M.

doi:10.1128/iai.01280-08

Cited by 110 publications

(160 citation statements)

References 55 publications

(55 reference statements)

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“…In two separate experiments, we found (data not presented) that, on average, the lptA::spc mutant exhibited increased susceptibility to 16 g/ml of LL-37 (5% survival) compared to the susceptibilities of the wild-type and C=lptA mutant strains (25% and 35% survival, respectively); the scrambled peptide did not exhibit bactericidal action against any of the test strains. This finding is consistent with earlier results that showed that lptA null mutants are more susceptible than wild-type gonococci to PMB (14,17).…”

Section: Resultssupporting

confidence: 83%

“…The increased fitness of the C=lptA mutant relative to the wild-type strain may be due to higher expression of the lptA gene in the C=lptA mutant. In this strain, the complementing lptA gene is under the control of the lac promoter (14), and increased expression of isopropyl-␤-Dthiogalactopyranoside (IPTG)-inducible genes has been demonstrated previously during murine infection (17,31). These results suggest that the PEA moiety on wild-type lipid A is beneficial to N. gonorrhoeae during infection and provides a fitness advantage over the fitness of gonococci devoid of PEA-decorated lipid A.…”

Section: Resultsmentioning

confidence: 66%

“…Wild-type N. gonorrhoeae strain FA19, an isogenic lptA::spc mutant, and a complemented lptA (C=lptA) mutant containing the wild-type lptA gene from strain FA19 were the primary test strains and have been described previously (14). The lptA mutant and C=lptA mutant are spectinomycin (Spc) resistant due to the inactivation of the lptA gene with a spectinomycin resistance (spc) gene (14). Streptomycin (Sm)-resistant derivatives of these strains were constructed as described previously (23).…”

Section: Methodsmentioning

confidence: 99%

“…Variations in surface structures can influence interactions between microbes and the host, and in the pathogenic neisseriae, phosphoethanolamine (PEA) substitution at the 4= position of lipid A increases resistance to polymyxin B (PMB), a bacteriumderived CAMP (14). PEA decoration of heptose II of the oligosac-charide core of the lipooligosaccharide (LOS) ␤-chain, in contrast, reduces resistance to PMB in Neisseria meningitidis but has no effect in N. gonorrhoeae.…”

mentioning

confidence: 99%

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Phosphoethanolamine Decoration of Neisseria gonorrhoeae Lipid A Plays a Dual Immunostimulatory and Protective Role during Experimental Genital Tract Infection

et al. 2014

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eThe induction of an intense inflammatory response by Neisseria gonorrhoeae and the persistence of this pathogen in the presence of innate effectors is a fascinating aspect of gonorrhea. Phosphoethanolamine (PEA) decoration of lipid A increases gonococcal resistance to complement-mediated bacteriolysis and cationic antimicrobial peptides (CAMPs), and recently we reported that wild-type N. gonorrhoeae strain FA1090 has a survival advantage relative to a PEA transferase A (lptA) mutant in the human urethral-challenge and murine lower genital tract infection models. Here we tested the immunostimulatory role of this lipid A modification. Purified lipooligosaccharide (LOS) containing lipid A devoid of the PEA modification and an lptA mutant of strain FA19 induced significantly lower levels of NF-B in human embryonic kidney Toll-like receptor 4 (TLR4) cells and murine embryonic fibroblasts than wild-type LOS of the parent strain. Moreover, vaginal proinflammatory cytokines and chemokines were not elevated in female mice infected with the isogenic lptA mutant, in contrast to mice infected with the wild-type and complemented lptA mutant bacteria. We also demonstrated that lptA mutant bacteria were more susceptible to human and murine cathelicidins due to increased binding by these peptides and that the differential induction of NF-B by wild-type and unmodified lipid A was more pronounced in the presence of CAMPs. This work demonstrates that PEA decoration of lipid A plays both protective and immunostimulatory roles and that host-derived CAMPs may further reduce the capacity of PEA-deficient lipid A to interact with TLR4 during infection.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Phosphoethanolamine Decoration of Neisseria gonorrhoeae Lipid A Plays a Dual Immunostimulatory and Protective Role during Experimental Genital Tract Infection

et al. 2014

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“…Modification of lipid A with PEA has been found to increase the resistance of N. gonorrhoeae to complement killing in normal human serum by increasing the binding of the complement regulatory protein C4b-binding protein and increasing resistance to endogenous cationic antimicrobial peptides (41,42). In N. meningitidis, modification of lipid A with PEA has been shown to inhibit bactericidal activity of cathepsin G within neutrophil extracellular traps (4) and to increase the adhesion of the bacteria to human cells (5).…”

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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Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

Lewis

Ram

2020

FEBS Letters

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Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, while Neisseria meningitidis is an important cause of bacterial meningitis and sepsis. Complement is a central arm of innate immune defenses and plays an important role in combating Neisserial infections. Persons with congenital and acquired defects in complement are at a significantly higher risk for invasive Neisserial infections such as invasive meningococcal disease and disseminated gonococcal infection compared to the general population. Of note, Neisseria gonorrhoeae and Neisseria meningitidis can only infect humans, which in part may be related to their ability to evade only human complement. This review summarizes the epidemiologic and clinical aspects of Neisserial infections in persons with defects in the complement system. Mechanisms used by these pathogens to subvert killing by complement and preclinical studies showing how these complement evasion strategies may be used to counteract the global threat of meningococcal and gonococcal infections are discussed.

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Phosphoethanolamine Substitution of Lipid A and Resistance ofNeisseria gonorrhoeaeto Cationic Antimicrobial Peptides and Complement-Mediated Killing by Normal Human Serum

Cited by 110 publications

References 55 publications

Phosphoethanolamine Decoration of Neisseria gonorrhoeae Lipid A Plays a Dual Immunostimulatory and Protective Role during Experimental Genital Tract Infection

Phosphoethanolamine Decoration of Neisseria gonorrhoeae Lipid A Plays a Dual Immunostimulatory and Protective Role during Experimental Genital Tract Infection

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

Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

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