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Previous data have indicated that the opc gene encoding an immunogenic invasin is specific to Neisseria meningitidis (Nm) and is lacking in Neisseria gonorrhoeae (Ng). The data presented here show that Nm and Ng both contain two paralogous opc-like genes, opcA, corresponding to the former opc gene, and (psi)opcB, a pseudogene. The predicted OpcA and OpcB proteins possess transmembrane regions with conserved non-polar faces but differ extensively in four of the five surface-exposed loops. Gonococcal OpcA was expressed weakly under in vitro conditions, and it is unknown whether these bacteria can express this protein at high levels. Analysis of the sequences flanking opcA and (psi)opcB revealed a framework of conserved housekeeping genes interspersed with DNA islands. These regions also contained several pseudogenes, deletions and IS elements, attesting to considerable genome plasticity. Both opcA and (psi)opcB are located on DNA islands that have probably been imported from unrelated bacteria. A third island encodes the dcmD/dcrD R/M genes in Ng versus a small open reading frame in most strains of Nm. Rare strains of Nm were identified in which the R/M island has been imported. DNA islands in Nm and Ng seem to have been acquired by recombination via conserved flanking housekeeping genes rather than by insertion of mobile genetic elements.
Mol Microbiol 1999 Aug
PMID:The opcA and (psi)opcB regions in Neisseria: genes, pseudogenes, deletions, insertion elements and DNA islands. 1041 53

The mtr (multiple transferable resistance) gene complex in Neisseria gonorrhoeae encodes an energy-dependent efflux pump composed of the MtrC-MtrD-MtrE cell envelope proteins that serves to export structurally diverse antimicrobial, hydrophobic agents (HAs). Many of these agents have membrane-acting detergent activity. Using Triton X-100 (TX-100) as a representative HA, we found that the mtrCDE efflux pump operon could be induced to higher levels of expression when an HA-sensitive strain was exposed to sublethal concentrations of this non-ionic detergent and the structurally related spermicide, nonoxynol-9. This induction was at the level of mtrCDE gene transcription and was independent of the MtrR repressor, which normally decreases mtrCDE gene expression. However, the enhanced resistance of gonococci to TX-100 was dependent on the expression of a previously undescribed gonococcal protein that belonged to the AraC/XylS family of transcriptional activators. We have termed this protein MtrA to signify its likely role in the activation of mtrCDE gene expression. Taken together with previous studies dealing with the genetic control of mtrCDE gene expression, we propose that gonococci can modulate their resistance to HAs through both positive and negative transcriptional control processes. The action of these regulatory processes is probably of importance in determining the survival capacity of gonococci at mucosal surfaces that contain detergent-like HAs.
Mol Microbiol 1999 Aug
PMID:Induction of the mtrCDE-encoded efflux pump system of Neisseria gonorrhoeae requires MtrA, an AraC-like protein. 1041 54

Gonococci often infect mucosal surfaces bathed in antibacterial fatty acids (FAs). Resistance of gonococci to FAs and other antibacterial hydrophobic agents has been attributed to the mtrCDE-encoded efflux pump system and a heretofore undefined mechanism. This alternative resistance mechanism has been suggested to mediate gonococcal resistance to long-chained FAs independently of the mtr efflux pump. We have now identified this alternative FA resistance system in gonococci and report that it bears significant similarity to the emrAB-encoded efflux pump possessed by Escherichia coli and the vceAB-encoded pump of Vibrio cholerae. We termed the gonococcal version of this efflux pump farAB (fatty acid resistance) to signify its involvement in FA resistance expressed by gonococci and to distinguish it from the emrAB- or vceAB-encoded pumps that modulate bacterial susceptibility to uncoupling agents and certain antibiotics. Although the farAB system in gonococci was found to provide resistance to FAs independently of the mtrCDE-encoded efflux pump, its function was dependent on the MtrE outer membrane protein. Moreover, expression of the tandemly linked farA and farB genes was positively associated with the presence of the MtrR transcriptional regulatory protein that normally downregulates the expression of mtrCDE. Thus, the data presented herein suggest that, while the mtrCDE- and farAB-encoded systems act independently to mediate resistance of gonococci to host-derived, hydrophobic antimicrobial agents, their capacity to export these agents is dependent on the same outer membrane protein (MtrE), and their expression may be differentially controlled by the same transcriptional regulatory protein (MtrR).
Mol Microbiol 1999 Aug
PMID:The farAB-encoded efflux pump mediates resistance of gonococci to long-chained antibacterial fatty acids. 1044 92

Infection of the endometrium by Neisseria gonorrhoeae is a pivotal stage in the development of pelvic inflammatory disease in women. An ex vivo model of cultures of primary human endometrial cells was developed to study gonococcal-host cell interactions. To facilitate these studies, gonococci were transformed with a hybrid shuttle vector containing the gfp gene from Aequoria victoria, encoding the green fluorescent protein (GFP), to produce intrinsically fluorescent bacteria. The model demonstrated that both pili and Opa proteins were important for both mediating gonococcal interactions with endometrial cells and inducing the secretion of pro-inflammatory cytokines and chemokines. Pil+ gonococci showed high levels of adherence and invasion, regardless of Opa expression, which was associated with increased secretion of IL-8 chemokine and reduced secretion of IL-6 cytokine. Gonococcal challenge also caused increased secretion of TNF-alpha cytokine, but this did not correlate with expression of pili or Opa, suggesting that release of components from non-adherent bacteria may be involved in TNF-alpha induction. Thus, the use of cultured primary endometrial cells, together with gonococci expressing green fluorescent protein, has the potential to extend significantly our knowledge, at the molecular level, of the role of this important human pathogen in the immunobiology of pelvic inflammatory disease.
Mol Microbiol 2000 Jan
PMID:Interaction of primary human endometrial cells with Neisseria gonorrhoeae expressing green fluorescent protein. 1063 75

Neisseria gonorrhoeae and Neisseria meningitidis have evolved intricate mechanisms to evade complement-mediated killing. Sialylation of gonococcal lipooligosaccharide (LOS) results in conversion of previously serum sensitive strains to unstable serum resistance, which is mediated by factor H binding. Porin (Por) is also instrumental in mediating stable serum resistance in gonococci. The 5th loop of certain gonococcal PorlAs binds factor H, which efficiently inactivates C3b to iC3b. Factor H glycan residues may be essential for factor H binding to certain Por1A strains. Por1A strains can also regulate the classical pathway by binding to C4b-binding protein (C4bp) probably via the 1st loop of the Por molecule. Certain serum resistant Por1 B strains can also regulate complement by binding C4bp through a loop other than loop 1. Purified C4b can inhibit binding of C4bp to Por 1B, but not Por1A, suggesting different binding sites on C4bp for the two Por types. Unlike serum resistant gonococci, resistant meningococci have abundant C3b on their surface, which is only partially processed to iC3b. The main mechanism of complement evasion by group B meningococci is inhibition of membrane attack complex (MAC) insertion by their polysaccharide capsule. LOS structure may act in concert with capsule to prevent MAC insertion. Meningococcal strains with Class 3 Por preferentially bind factor H, suggesting Class 3 Por acts as a receptor for factor H.
Mol Immunol
PMID:The contrasting mechanisms of serum resistance of Neisseria gonorrhoeae and group B Neisseria meningitidis. 1069 46

The porB locus codes for the major outer membrane protein of Neisseria gonorrhoeae. Alleles of this locus have been assigned to two homology groups based on close sequence and immunological relationships and are designated as either PIA or PIB. Several population parameters were estimated and compared among these two groups using a data set of 22 PIA sequences and 91 PIB sequences obtained from diverse geographic localities and from time periods spanning approximately 50 years. Recombination appears to be extensive in the porB gene. While the recombination rates are similar for the PIA and PIB sequences, the relative contribution of recombination to genetic diversity is higher for the PIA sequences. Alleles belonging to the PIB group show greater genetic diversity than do those in the PIA group. Although phylogenetic analysis did not reveal temporal or geographic clustering of sequences, estimates of gene flow and the fixation index suggested that PIB sequences exhibit population substructure based on geographic locality. Selection acts in these homology groups in a different way. While positive Darwinian selection is the dominant force driving the evolution of the PIA sequences, purifying selection operates also on the PIB sequences. These differences may be attributable to the greater propensity of PIA strains, as compared with PIB strains, to cause disseminated gonococcal infection, which would expose the former to intense selection pressure from the host immune system. The molecular evolution of Neisseria gonorrhoeae seems to be driven by the simultaneous action of selection and recombination, but under different rates and selection pressures for the PIA and PIB homology groups.
Mol Biol Evol 2000 Mar
PMID:Population genetics of the porB gene of Neisseria gonorrhoeae: different dynamics in different homology groups. 1072 43

FetA, the recently characterized gonococcal ferric enterobactin receptor, exhibited extremely rapid phase variation between high- and low-expression levels. The frequency of phase variation was approximately 1.3% in both directions in gonococcal strain FA1090. FetA expression in the 'high phase' was significantly greater than the level of expression in the 'low phase'. Expression levels correlated with the number of cytosine residues in a string of cytosines located close to the transcriptional start site for fetA between the putative -10 and -35 consensus sequences. Antibody production against FetA commonly occurs in infected patients, and we therefore hypothesize that phase variation reflects a balance between the advantages of being able to use a ferric siderophore as an iron source and evasion of the host immune response.
Mol Microbiol 2000 May
PMID:Phase variation of the gonococcal siderophore receptor FetA. 1084 48

In the present study, we show that Neisseria gonorrhoeae lipooligosaccharide (LOS) can bind to the asialoglycoprotein receptor (ASGP-R) on human sperm. This work demonstrates the presence of ASGP-R on human sperm. Binding of purified ASGP-R ligand decreased in the presence of gonococci. Binding of purified iodinated gonococcal LOS identified a protein of molecular weight corresponding to that of human ASGP-R. The presence of excess unlabelled LOS blocked binding of iodinated gonococcal LOS. Binding of wild-type gonococcal LOS to sperm was higher than that of mutant LOS lacking the galactose ligand for ASGP-R. These data suggest that the ASGP-R on human sperm cells recognizes and binds wild-type gonococcal LOS. This interaction may contribute to the transmission of gonorrhea from infected males to their sexual partners.
Mol Microbiol 2000 Jun
PMID:Gonococcal lipooligosaccharide is a ligand for the asialoglycoprotein receptor on human sperm. 1084 91

Analysis of the Neisseria gonorrhoeae DNA sequence database revealed the presence of two genes, one encoding a protein predicted to be 37. 5% identical (50% similar) in amino acid sequence to the Escherichia coli FNR protein and the other encoding a protein 41% and 42% identical (54 and 51% sequence similarity) to the E. coli NarL and NarP proteins respectively. Both genes have been cloned into E. coli and insertionally inactivated in vitro. The mutated genes have been transformed into gonococci and recombined into the chromosome. The fnr mutation totally abolished and the narP mutation severely diminished the ability of gonococci to: (i) grow anaerobically; (ii) adapt to oxygen-limited growth; (iii) initiate transcription from the aniA promoter (which directs the expression of a copper-containing nitrite reductase, AniA, in response to the presence of nitrite); and (iv) reduce nitrite during growth in oxygen-limited media. The product of nitrite reduction was identified to be nitrous oxide. Immediately upstream of the narL/narP gene is an open reading frame that, if translated, would encode a homologue of the E. coli nitrate- and nitrite-sensing proteins NarX and NarQ. As transcription from the aniA promoter was not activated during oxygen-limited growth in the presence of nitrate, the gonococcal two-component regulatory system is designated NarQ-NarP rather than NarX-NarL. As far as we are aware, this is the first well-documented example of a two-component regulatory system working in partnership with a transcription activator in pathogenic neisseria. A 45 kDa c-type cytochrome that was synthesized during oxygen-limited, but not during oxygen sufficient, growth was identified as a homologue of cytochrome c peroxidases (CCP) of other bacteria. The gene for this cytochrome, designated ccp, was located, and its regulatory region was cloned into the promoter probe vector pLES94. Transcription from the ccp promoter was repressed during aerobic growth and induced during oxygen-limited growth and was totally FNR dependent, suggesting that the gonococcal FNR protein is a transcription activator of at least two genes. However, unlike AniA, synthesis of the CCP homologue was insensitive to the presence of nitrite during oxygen-limited growth.
Mol Microbiol 2000 Aug
PMID:Identification of transcription activators that regulate gonococcal adaptation from aerobic to anaerobic or oxygen-limited growth. 1097 6

The pilus of Neisseria gonorrhoeae (the gonococcus Gc), the causative agent of gonorrhoea, promotes attachment of the gonococcus to the host epithelium and is essential for the establishment of disease. The ability of N. gonorrhoeae to infect previously exposed individuals is partially due to pilus antigenic variation. In addition, variation of the pilus has been proposed to function in the adaptation of the gonococcus to host environments. Previously, we described the development of a competitive reverse transcriptase (RT)-PCR assay that quantifies the frequency of pilin antigenic variation within a gonococcal population. Using this assay, the effect of different biologically relevant environmental conditions on the frequency of pilin antigenic variation was tested. Of the environmental conditions examined in vitro, only limited iron affected a significant change in the frequency of antigenic variation. Further investigation revealed that an observed increase in pilin antigenic variation reflected an increase in other DNA recombination and DNA repair processes within iron-starved cultures. In addition, this low iron-induced increase was determined to be independent of changes in RecA expression and was observed in a Fur mutant strain. As gonococci encounter conditions of low iron during infection, these data suggest that iron-limitation signals for increased recombinational events that are important for gonococcal pathogenesis.
Mol Microbiol 2000 Sep
PMID:Iron availability regulates DNA recombination in Neisseria gonorrhoeae. 1097 26


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