Clinically relevant mutations that cause derepression of the <i>Neisseria gonorrhoeae</i> MtrC‐MtrD‐MtrE Efflux pump system confer different levels of antimicrobial resistance and <i>in vivo</i> fitness

Warner, Douglas M.; Shafer, William M.; Jerse, Ann E.

doi:10.1111/j.1365-2958.2008.06424.x

Cited by 188 publications

(200 citation statements)

References 65 publications

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“…Interestingly, PEA decoration of lipid A also protects Salmonella enterica serovar Typhimurium (39), Acinetobacter baumannii (40), and N. meningitidis from CAMPs (16). In N. gonorrhoeae, CAMPs are also expelled through the gonococcal MtrC-MtrD-MtrE active efflux pump (26,41), which is a critical virulence factor in the mouse infection model (23).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…The difference in antibiotic sensitivity between the two strains is partially the result of differential induction of the MtrCDE efflux pump between the two strains. In MS11, the efflux pump is upregulated relative to other strains of N. gonorrhoeae (52), whereas in FA1090, the pump is downregulated due to a mutation in the inducer, mtrA (35), resulting in different sensitivities of the strains to a variety of antimicrobials.…”

Section: Survival Of Recb and Recd Mutants In Fa1090 And Ms11mentioning

confidence: 99%

Pilin Antigenic Variation Occurs Independently of the RecBCD Pathway in Neisseria gonorrhoeae

Helm

Seifert

2009

J Bacteriol

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Type IV pilus expression has been strongly implicated in the virulence of Neisseria gonorrhoeae, the causative agent of gonorrhea. In Neisseria, these pili undergo frequent antigenic variation (Av), which is presumed to allow reinfection of high-risk groups. Pilin Av is the result of RecA-mediated recombination events between the gene encoding the major pilin subunit (pilE) and multiple silent pilin locus (pilS) copies, utilizing a RecF-like recombination pathway. The role of RecBCD in pilin Av has been controversial. Previous studies measuring pilin Av in recB and recD mutants in two independent strains of N. gonorrhoeae (MS11 and FA1090) by indirect methods yielded conflicting results. In addition, these two laboratory strains have been suggested to express very different DNA repair capabilities. We show that the FA1090 and MS11 parental strains have similar abilities to repair DNA damage via UV-induced DNA damage, nalidixic acid-induced double-strand breaks, and methyl methanesulfonate-induced alkylation and that RecB and RecD are involved in the repair of these lesions. To test the role of the RecBCD pathway in pilin Av, the rate and frequency of pilin Av were directly measured by sequencing the pilE locus in randomly selected piliated progeny of both MS11 and FA1090 in recB and recD mutants. Our results definitively show that recB and recD mutants undergo pilin Av at rates similar to those of the parents in both strain backgrounds, demonstrating that efficient pilin Av is neither enhanced nor inhibited by the RecBCD complex.Homologous recombination is a widely conserved process used by all organisms to repair DNA damage and to mediate genetic transfer. Usually RecA or a RecA homologue is required for homologous recombination, but the other processing enzymes used to prepare DNA for recombination differ between organisms. Generally, double-stranded DNA (dsDNA) breaks are repaired by the RecBCD complex in gram-negative organisms and the AddAB complex in gram-positive organisms, although exceptions exist in which AddAB has been found in some proteobacteria (1,4,29,33,56). Single-stranded DNA (ssDNA) gaps are typically repaired by the RecF pathway, which is ubiquitous among the Bacteria and is part of a universal step in recombinational repair (31). While the RecBCD and RecF pathways have been extensively studied in Escherichia coli, they are less well understood in the humanspecific pathogen Neisseria gonorrhoeae. N. gonorrhoeae is a gram-negative bacterium that has been isolated only from infected humans and is believed to exist naturally only within the human population. Like E. coli, N. gonorrhoeae has a RecA homologue and possesses most of the genes that define the RecBCD and RecF pathways of E. coli (27).In E. coli, the RecBCD exonuclease begins to degrade DNA at the site of the break, and upon reaching a particular sequence, a chi site, the RecD component is inactivated, leaving RecBC to act as a helicase, processively unwinding the DNA, yielding ssDNA, which is the substrate for RecA (reviewed in refere...

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“…The N. gonorrhoeae MtrCDE efflux pump provides protection from heme and other hydrophobic agents (9,37). Clinically relevant mutations that result in the overexpression of the MtrCDE efflux pump generally result in increased resistance to hydrophobic agents and, correspondingly, increased bacterial burden in vaginal lavage fluids of infected mice (124). Those authors proposed that the direct relationship between virulence and MtrCDE expression levels is due to increased resistance to innate immune effectors.…”

Section: Role Of Heme In Pathogenesismentioning

confidence: 99%

Overcoming the Heme Paradox: Heme Toxicity and Tolerance in Bacterial Pathogens

2010

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Virtually all bacterial pathogens require iron to infect vertebrates. The most abundant source of iron within vertebrates is in the form of heme as a cofactor of hemoproteins. Many bacterial pathogens have elegant systems dedicated to the acquisition of heme from host hemoproteins. Once internalized, heme is either degraded to release free iron or used intact as a cofactor in catalases, cytochromes, and other bacterial hemoproteins. Paradoxically, the high redox potential of heme makes it a liability, as heme is toxic at high concentrations. Although a variety of mechanisms have been proposed to explain heme toxicity, the mechanisms by which heme kills bacteria are not well understood. Nonetheless, bacteria employ various strategies to protect against and eliminate heme toxicity. Factors involved in heme acquisition and detoxification have been found to contribute to virulence, underscoring the physiological relevance of heme stress during pathogenesis. Herein we describe the current understanding of the mechanisms of heme toxicity and how bacterial pathogens overcome the heme paradox during infection.

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Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC‐MtrD‐MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness

Cited by 188 publications

References 65 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

Pilin Antigenic Variation Occurs Independently of the RecBCD Pathway in Neisseria gonorrhoeae

Overcoming the Heme Paradox: Heme Toxicity and Tolerance in Bacterial Pathogens

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