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Six synthetic 25-mer peptides corresponding to certain presumed surface-exposed regions of gonococcal porin protein I (PI) were made from strains FA19 (PIA) and MS11 (PIB). Four peptides were immunogenic in rabbits. Affinity-purified antisera against both PIA and PIB N-terminal peptides were bactericidal for homologous gonococci and many heterologous PI serovars. However, sialylation of gonococcal lipopolysaccharide (LPS) by growth of gonococci in the presence of cytidine monophosphate-neuraminic acid (CMP-NANA) abrogated the bactericidal activity of these antisera. Binding of anti-PI monoclonal antibodies to whole gonococci was reduced two- to fourfold by sialylation of LPS, suggesting that sialylation may inhibit bactericidal activity by masking porin epitopes. However, binding of anti-PII (Opa) monoclonal antibodies was not inhibited, yet complement-mediated killing was inhibited by sialylated LPS. Binding of complement components C3 and C9 was inhibited in the presence of either anti-PI or anti-PII monoclonals when gonococci were grown in the presence of CMP-NANA. Thus sialylation inhibited both anti-PI antibody binding and complement deposition, with a resultant decrease in bactericidal activity.
Mol Microbiol 1992 Sep
PMID:Antibodies to N-terminal peptides of gonococcal porin are bactericidal when gonococcal lipopolysaccharide is not sialylated. 128 Mar 17

Pilin variation in Neisseria gonorrhoeae depends on a family of variant genes that undergo homologous, intragenic recombination. This work focuses on the repertoire of silent variant pilin genes in strain MS11, which contribute to the extensive variation of the expressed gene copy. A total of 17 silent copies were identified, which are, to varying degrees, truncated at their 5' coding region and grouped in seven distinct pil loci. Most silent copies belong to loci pilS1, pilS2 and pilS6, which contain six, two and three silent copies, respectively, tandemly arranged. The pilS5 and pilS7 loci each contain only a single copy. In addition, two silent copies are associated with each of the two pilE loci. By comparison with sequences present in the expressed gene of other variants of the same strain, it is suggested that each silent locus is capable of donating variant sequences into the expression locus and, thus, each silent copy can contribute to the variability of pilin expression. Often, concomitant with changes in the expressed copy, the silent copies of the pilE1 locus undergo recombinations as well. Analyses of unrelated clinical isolates of N. gonorrhoeae reveal homologies of hypervariant pilin sequences with those present in strain MS11, suggesting a limited diversity of such sequences within the gonococcal population and the existence of substantial functional constraints on the variability of pilin and pili. The data further indicate that hypervariant pilin sequences are subject to horizontal exchange and interstrain recombination.
Mol Microbiol 1992 Jan
PMID:Silent pilin genes of Neisseria gonorrhoeae MS11 and the occurrence of related hypervariant sequences among other gonococcal isolates. 134 37

Pili confer the initial ability of Neisseria gonorrhoeae to bind to epithelial cells. Pilin (PilE), the major pilus subunit, and a minor protein termed PilC, reportedly essential for pilus biogenesis, undergo intra-strain phase and structural variation. We demonstrate here that at least two different adherence properties are associated with the gonococcal pili: one is specific for erythrocytes, which is virtually unaffected by PilE variation, and another is specific for epithelial cells, and is modulated in response to the variation of PilE. Based on this finding, mutants of a recA- strain were selected that had lost the ability to bind to human cornea epithelial cells (A-) but retained the ability to form pili (P+) and to agglutinate human erythrocytes (H+). The adherence-negative mutants failed to produce detectable levels of PilC1 or PilC2 proteins, representing piIC phase variants generated in the absence of RecA. The A- pilC phase variants were indistinguishable from their A+ parents and spontaneous A+ revertants with regard to the amount of PilE produced and its electrophoretic mobility, the degrees of piliation and haemagglutination, and the pilE nucleotide sequence. These data demonstrate a central role for PilC in pilus-mediated adherence of N. gonorrhoeae to human epithelial cells and further indicate that neither PilC1 nor PilC2 is obligatory for the assembly of gonococcal pili.
Mol Microbiol 1992 Nov
PMID:Interaction of two variable proteins (PilE and PilC) required for pilus-mediated adherence of Neisseria gonorrhoeae to human epithelial cells. 136 47

Studies of natural populations of Neisseria meningitidis using multilocus enzyme electrophoresis have shown extensive genetic variation within this species, which, it has been proposed, implies a level of sequence diversity within meningococci that is greater than that normally considered as the criterion for species limits in bacteria. To obtain a direct measure of the sequence diversity among meningococci, we obtained the nucleotide sequences of most of the argF, recA and fbp genes of eight meningococci of widely differing electrophoretic type (from the reference collection of Caugant). Sequence variation between the meningococcal strains ranged from 0-0.6% for fbp, 0-1.3% for argF, and 0-3.3% for recA. These levels of diversity are no greater than those found within Escherichia coli 'housekeeping' genes and suggest that multilocus enzyme electrophoresis may overestimate the extent of nucleotide sequence diversity within meningococci. The average sequence divergence between the Neisseria meningitidis strains and N. gonorrhoeae strain FA19 was 1.0% for fbp and 1.6% for recA. The argF gene, although very uniform among the eight meningococcal isolates, had a striking mosaic structure when compared with the gonococcal argF gene: two regions of the gene differed by greater than 13% in nucleotide sequence between meningococci and gonococci, whereas the rest of the gene differed by less than 1.7%. One of the diverged regions was shown to have been introduced from the argF gene of a commensal Neisseria species that is closely related to Neisseria cinerea. The source of the other region was unclear.
Mol Microbiol 1992 Aug
PMID:Sequence diversity within the argF, fbp and recA genes of natural isolates of Neisseria meningitidis: interspecies recombination within the argF gene. 140 54

We studied the interaction of normal human serum immunoglobulins with outer-membrane bleb antigens of Neisseria gonorrhoeae. Gonococcal 68,000 Dalton and Lip (H.8 antigen) outer-membrane proteins were recognized by normal human serum immunoglobulins in blebs from serum-resistant strains, but not in blebs from serum-susceptible strains. The addition of blebs from a serum-resistant strain to bactericidal assays resulted in significantly greater inhibition of serum killing than the addition of blebs from a serum-susceptible strain. Our results indicate that blebs from two serum-resistant gonococcal strains have an enhanced ability to bind and remove cell-targeted bactericidal factors, and that outer-membrane blebbing may contribute to serum resistance.
Mol Microbiol 1992 Mar
PMID:The interaction of naturally elaborated blebs from serum-susceptible and serum-resistant strains of Neisseria gonorrhoeae with normal human serum. 157 2

Members of the opacity-associated (Opa) outer membrane protein family of Neisseria gonorrhoeae have been proposed to mediate adherence to and invasion of cultured human epithelial cells. We transformed Escherichia coli with a plasmid containing a gonococcal opa gene fused in-frame to the leader sequence of the beta-lactamase gene as described by Palmer et al. [Palmer, L., Brooks, G. F. & Falkow, S. (1989) Mol. Microbiol. 3, 663-671]. These transformed E. coli [E. coli (opa)] expressed the heat-modifiable opa gene product (the Opa protein) in their outer membrane and adhered to and invaded ME-180 human endocervical epithelial cells. In a 2-h adherence assay, an average of 26.7 E. coli (opa) adhered per ME-180 cell, whereas the control E. coli carrying only the expression vector (pKT279) did not adhere at all (less than 0.15 bacterium per cell). We investigated the ability of the adherent E. coli (opa) to invade ME-180 epithelial cells by using a gentamicin selection assay. We recovered up to 1 x 10(6) gentamicin-resistant bacteria per monolayer when ME-180 cells were infected with E. coli (opa) compared to less than 10 bacteria when the epithelial cells were infected with the same number of control E. coli (pKT279). The kinetics and level of invasion by E. coli (opa) were similar to invasion by Opa+ N. gonorrhoeae. Maximum invasion occurred 4 h after infection with 4 x 10(7) bacteria. Transmission electron microscopy studies confirmed that E. coli (opa) invaded ME-180 cells. In comparative studies, the number of E. coli (opa) that invaded HEC-1-B human endometrial epithelial cells was about an order of magnitude less than the number that invaded ME-180 cells, and E. coli (opa) did not invade Chang human conjunctival epithelial cells at all. The observations that early (less than 4 h) invasion by E. coli (opa) was dramatically inhibited, in a dose-responsive manner, by the actin-disrupting reagent cytochalasin D but later invasion (8-24 h) was not suggest that invasion mediated by Opa proteins may occur by two mechanisms, only one of which is dependent upon microfilament function. Transmission electron microscopy also revealed that infected epithelial cells had a dramatically increased amount of cytoplasmic fibrillar material surrounding the nucleus. The function and genesis of this material remain unclear. These studies indicate that at least one gonococcal Opa protein is an invasin.
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PMID:Escherichia coli expressing a Neisseria gonorrhoeae opacity-associated outer membrane protein invade human cervical and endometrial epithelial cell lines. 160 63

Interactions of human neutrophils with recombinant Escherichia coli expressing gonococcal outer membrane Opa proteins were examined using chemiluminescent and biological assays. Seven opa loci from Neisseria gonorrhoeae MS11 4.8 were expressed as beta-lactamase-Opa fusion proteins that contained all but the mature N-terminal amino acid of the full-length Opa protein fused to three N-terminal amino acids derived from the mature beta-lactamase. The Opa fusion proteins were exported and assembled in the outer membrane of E. coli in a manner similar to that of Opa in N. gonorrhoeae, as evaluated by antibody binding and in situ proteolytic cleavage. All fusion proteins exhibited the characteristic heat-modifiable migration in SDS-polyacrylamide gel electrophoresis that typifies Opa proteins of neisseriae. Opa fusion proteins conferred on E. coli the ability to stimulate a chemiluminescent response from human neutrophils in the absence of antibody or complement. The nature of the response in terms of chemiluminescence, phagocytosis, and killing was in all cases analogous to that seen using N. gonorrhoeae expressing the equivalent Opa protein. Neither E. coli nor gonococci expressing OpaA elicited a response from neutrophils. Use of E. coli expressing Opa fusions should be useful in defining their biological activities and pathogenic roles.
Mol Microbiol 1992 Jul
PMID:Human neutrophil response to recombinant neisserial Opa proteins. 163 Mar 13

Since Neisseria gonorrhoeae is an obligate pathogen, there is no animal model for identification of virulence factors for this bacterium. An alternative model for assessment of gonococcal virulence is invasion of the adenocarcinoma endometrial cell line, HecIB. Preincubation of gonococci with glutaraldehyde-fixed HecIB cells eliminated the six- to eight-hour lag in entry of bacteria into a fresh HeIIB monolayer seen with unpreincubated gonococci or gonococci preincubated in tissue-culture medium alone. Gonococci tightly bound to fixed HecIB cells were more invasive than cells free in the tissue-culture medium, suggesting that actual contact with HecIB cells was required for the enhancement of invasive ability. Chloramphenicol addition during the preincubation prevented the enhanced invasion. Preincubated gonococci were not more adherent to HecIB cells, suggesting that a stage in invasion after binding of gonococci to HecIB cells was enhanced. The enhanced invasion occurred only when gonococci were preincubated with HecIB cells and not with HEp-2, HeLa, Chang or CHO cells. This eukaryotic cell specificity for induction of enhanced invasion may indicate a role for invasion in gonococcal infection of the endometrium.
Mol Microbiol 1991 Jun
PMID:Enhancement of the invasive ability of Neisseria gonorrhoeae by contact with HecIB, an adenocarcinoma endometrial cell line. 178 1

The outer membrane of Neisseria gonorrhoeae contains a 44,000 dalton (44kDa) surface-exposed protein which has the reported ability to form covalent interactions with peptidoglycan (PG). This PG-binding outer-membrane protein (OMP) appears to be highly conserved since it has been detected in all isolates examined. It also appears to be invariant since its primary structure among strains gives evidence of being identical (Judd et al., 1991). While studying the interaction of gonococcal penicillin-binding proteins (PBPs) with human lysosomal cathepsin G, we noticed that the 44kDa PG-binding OMP exhibited certain properties similar to PBP3. In this study we sought to obtain biochemical evidence to ascertain whether these proteins were the same. We found that both proteins fractionated with other sarkosyl-insoluble OMPs and that they exhibited similar susceptibility to cleavage in situ by enzymatically active cathepsin G. Moreover, a purified preparation of the 44kDa OMP was found to covalently bind radiolabelled benzylpenicillin in vitro. Thus, the data presented herein suggest that the 44kDa PG-binding OMP and PBP3 are the same OMP.
Mol Microbiol 1991 May
PMID:Gonococcal penicillin-binding protein 3 and the surface-exposed 44kDa peptidoglycan-binding protein appear to be the same molecule. 195 87

This review discusses the genetic basis for surface changes in Neisseria gonorrhoeae and the role of specific transformation reactions in producing them. Variation in the structure of pilin, the subunit of gonococcal pili, occurs by transformation-mediated recombination of DNA segments in storage loci with the expression locus. These pilin loci have low recombination potential since their sequences contain only short uninterrupted identical sequences. The DNA within storage or silent loci are also relatively deficient in the short defined sequences which target DNA for efficient uptake and thus have relatively low affinity for the DNA transport system. Consequently, pilin-encoding DNA segments constitute relatively poor substrates for the general transformation system of gonococci. These considerations suggest the existence of locus-specific factors which increase the efficiency of genetic exchange between pilin loci. I raise the speculative hypothesis that one function of transformation-mediated DNA entry is to provide a regulatory stimulus signalling the death of neighbouring gonococci. This regulatory shift might lead to production of factors which accelerate genetic reshuffling of pilin loci either by transformation per se using external DNA as donor, or via a recombinational process which utilizes internally derived DNA segments as donors. A signalling function for transforming DNA also clarifies several general properties of specific transformation reactions.
Mol Microbiol 1990 Mar
PMID:The role of transformation in the variability of the Neisseria gonorrhoeae cell surface. 197 33


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