scholarly journals The Iron-Repressed, AraC-Like Regulator MpeR Activates Expression offetAin Neisseria gonorrhoeae

2011 ◽  
Vol 79 (12) ◽  
pp. 4764-4776 ◽  
Author(s):  
Aimee Hollander ◽  
Alexandra Dubon Mercante ◽  
William M. Shafer ◽  
Cynthia Nau Cornelissen
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Iron Transport ◽  
Reproductive Tract ◽  
Treatment Options ◽  
Effective Vaccine ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Treatment And Prevention ◽  
Resistance Rates

ABSTRACTNeisseria gonorrhoeaeis an obligate human pathogen that causes the common sexually transmitted infection gonorrhea. Gonococcal infections cause significant morbidity, particularly among women, as the organism ascends to the upper reproductive tract, resulting in pelvic inflammatory disease, ectopic pregnancy, and infertility. In the last few years, antibiotic resistance rates have risen dramatically, leading to severe restriction of treatment options for gonococcal disease. Gonococcal infections do not elicit protective immunity, nor is there an effective vaccine to prevent the disease. Thus, further understanding of the expression, function, and regulation of surface antigens could lead to better treatment and prevention modalities in the future. In the current study, we determined that an iron-repressed regulator, MpeR, interacted specifically with the DNA sequence upstream offetAand activated FetA expression. Interestingly, MpeR was previously shown to regulate the expression of gonococcal antimicrobial efflux systems. We confirmed that the outer membrane transporter FetA allows gonococcal strain FA1090 to utilize the xenosiderophore ferric enterobactin as an iron source. However, we further demonstrated that FetA has an extended range of substrates that encompasses other catecholate xenosiderophores, including ferric salmochelin and the dimers and trimers of dihydroxybenzoylserine. We demonstrated thatfetAis part of an iron-repressed, MpeR-activated operon which putatively encodes other iron transport proteins. This is the first study to describe a regulatory linkage between antimicrobial efflux and iron transport inN. gonorrhoeae. The regulatory nidus that links these systems, MpeR, is expressed exclusively by pathogenic neisseriae and is therefore expected to be an important virulence factor.

scholarly journals Transcriptomic Data Sets To Determine Gene Expression Changes Mediated by the Presence of PBT2 in Growth Medium of Multidrug-Resistant Neisseria gonorrhoeae WHO Z

2020 ◽  
Vol 9 (21) ◽  
Author(s):  
Freda E.-C. Jen ◽  
Ibrahim M. El-Deeb ◽  
John M. Atack ◽  
Mark von Itzstein ◽  
Michael P. Jennings
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Transcriptome Sequencing ◽  
Multidrug Resistant ◽  
Data Sets ◽  
Sequencing Data ◽  
Transmitted Infection ◽  
High Coverage ◽  
Content Type ◽  
Sexually Transmitted ◽  
Transcriptomic Data

ABSTRACT Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea. High-coverage (∼3,300-fold) transcriptome sequencing data have been collected from multidrug-resistant N. gonorrhoeae strain WHO Z grown in the presence and absence of PBT2.

scholarly journals Discovery of a New Neisseria gonorrhoeae Type IV Pilus Assembly Factor, TfpC

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Linda I. Hu ◽  
Shaohui Yin ◽  
Egon A. Ozer ◽  
Lee Sewell ◽  
Saima Rehman ◽  
...  
Keyword(s):  
Cell Surface ◽  
Neisseria Gonorrhoeae ◽  
Bacterial Cell ◽  
Bacterial Species ◽  
Type Iv Pili ◽  
Type Iv Pilus ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Type Iv

ABSTRACT Neisseria gonorrhoeae relies on type IV pili (T4p) to promote colonization of their human host and to cause the sexually transmitted infection gonorrhea. This organelle cycles through a process of extension and retraction back into the bacterial cell. Through a genetic screen, we identified the NGO0783 locus of N. gonorrhoeae strain FA1090 as containing a gene encoding a protein required to stabilize the type IV pilus in its extended, nonretracted conformation. We have named the gene tfpC and the protein TfpC. Deletion of tfpC produces a nonpiliated colony morphology, and immuno-transmission electron microscopy confirms that the pili are lost in the ΔtfpC mutant, although there is some pilin detected near the bacterial cell surface. A copy of the tfpC gene expressed from a lac promoter restores pilus expression and related phenotypes. A ΔtfpC mutant shows reduced levels of pilin protein, but complementation with a tfpC gene restored pilin to normal levels. Bioinformatic searches show that there are orthologues in numerous bacterial species, but not all type IV pilin-expressing bacteria contain orthologous genes. Coevolution and nuclear magnetic resonance (NMR) analysis indicates that TfpC contains an N-terminal transmembrane helix, a substantial extended/unstructured region, and a highly charged C-terminal coiled-coil domain. IMPORTANCE Most bacterial species express one or more extracellular organelles called pili/fimbriae that are required for many properties of each bacterial cell. The Neisseria gonorrhoeae type IV pilus is a major virulence and colonization factor for the sexually transmitted infection gonorrhea. We have discovered a new protein of Neisseria gonorrhoeae called TfpC that is required to maintain type IV pili on the bacterial cell surface. There are similar proteins found in other members of the Neisseria genus and many other bacterial species important for human health.

scholarly journals Sexually Transmitted Neisseria gonorrhoeae Infections—Update on Drug Treatment and Vaccine Development

Medicines ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 11
Author(s):  
Amber Jefferson ◽  
Amanda Smith ◽  
Pius S. Fasinu ◽  
Dorothea K. Thompson
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Vaccine Development ◽  
Target Identification ◽  
Treatment Options ◽  
New Drugs ◽  
Effective Vaccine ◽  
Sexually Transmitted ◽  
Successful Vaccine ◽  
Future Success ◽  
The Status

Background: Sexually transmitted gonorrhea, caused by the Gram-negative diplococcus Neisseria gonorrhoeae, continues to be a serious global health challenge despite efforts to eradicate it. Multidrug resistance among clinical N. gonorrhoeae isolates has limited treatment options, and attempts to develop vaccines have not been successful. Methods: A search of published literature was conducted, and information extracted to provide an update on the status of therapeutics and vaccine development for gonorrheal infection. Results: Recommended pharmacological treatment for gonorrhea has changed multiple times due to increasing acquisition of resistance to existing antibiotics by N. gonorrhoeae. Only broad-spectrum cephalosporin-based combination therapies are currently recommended for treatment of uncomplicated urogenital and anorectal gonococcal infections. With the reported emergence of ceftriaxone resistance, successful strategies addressing the global burden of gonorrhea must include vaccination. Century-old efforts at developing an effective vaccine against gonorrhea, leading to only four clinical trials, have not yielded any successful vaccine. Conclusions: While it is important to continue to explore new drugs for the treatment of gonorrhea, the historical trend of resistance acquisition suggests that any long-term strategy should include vaccine development. Advanced technologies in proteomics and in silico approaches to vaccine target identification may provide templates for future success.

scholarly journals Challenges and Controversies Concerning Neisseria gonorrhoeae-Neutrophil Interactions in Pathogenesis

mBio ◽  
2021 ◽  
Author(s):  
Alison K. Criss ◽  
Caroline A. Genco ◽  
Scott D. Gray-Owen ◽  
Ann E. Jerse ◽  
H Steven Seifert
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Sexually Transmitted Infection ◽  
Infection Rates ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted

The bacterium Neisseria gonorrhoeae (Ngo) is the main cause of the sexually transmitted infection gonorrhea. The global incidence of 87 million new Ngo infections each year, rising infection rates, and the emergence of Ngo strains that are resistant to all clinically recommended antibiotics have raised the specter of untreatable infections (M.

scholarly journals Men and Women Have Similar Neisseria gonorrhoeae Bacterial Loads: a Comparison of Three Anatomical Sites

2020 ◽  
Vol 58 (11) ◽  
Author(s):  
Brian M. J. W. van der Veer ◽  
Christian J. P. A. Hoebe ◽  
Nicole H. T. M. Dukers-Muijrers ◽  
Lieke B. van Alphen ◽  
Petra F. G. Wolffs
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Bacterial Load ◽  
Large Population ◽  
Transmitted Infection ◽  
Men And Women ◽  
Content Type ◽  
Transmission Potential ◽  
Sexually Transmitted ◽  
Standard Curve ◽  
Sex With Men

ABSTRACT Neisseria gonorrhoeae is a common bacterial sexually transmitted infection (STI). Currently, there are limited data on the bacterial load in both men and women and on both genital and extragenital sites. Therefore, we quantified N. gonorrhoeae bacterial loads in a large population of women, heterosexual men, and men who have sex with men (MSM) at three different anatomical sites. N. gonorrhoeae-positive samples (n = 1265) of STI clinic consultations (n = 944) were tested for N. gonorrhoeae with the Roche Cobas 4800 system, and quantification cycle (Cq) values were used as an inversely proportional measure for N. gonorrhoeae bacterial load after interpolation from a standard curve. Bacterial loads were compared between sample materials and sexes using t tests. The following mean N. gonorrhoeae loads were observed: urine, 4.5 ± 1.0 log10 CFU/ml; vaginal swabs, 4.3 ± 1.1 log10 CFU/ml; anorectal swabs (women), 4.0 ± 1.2 log10 CFU/ml; anorectal swabs (men), 4.5 ± 1.3 log10 CFU/ml; oropharyngeal swabs (women), 2.8 ± 0.9 log10 CFU/ml; and oropharyngeal swabs (men), 3.2 ± 1.0 log10 CFU/ml. Oropharyngeal swabs had a significantly lower N. gonorrhoeae load (P < 0.001) than genital and anorectal samples. Loads did not differ between men and women. This is the first study that determined N. gonorrhoeae load in both women and men at three anatomical sites. The substantial N. gonorrhoeae load at all sample sites suggest that all sites may have transmission potential. However, the oropharyngeal site presents the lowest bacterial load. Men and women have a similar N. gonorrhoeae loads on separate anatomical sites, arguing for similar transmission potential and similar clinical relevance.

scholarly journals Adaptation of Neisseria gonorrhoeae to the Female Reproductive Tract

2020 ◽  
Vol 13 ◽  
pp. 117863612094707
Author(s):  
Wenxia Song ◽  
Qian Yu ◽  
Liang-Chun Wang ◽  
Daniel C Stein
Keyword(s):  
Epithelial Cell ◽  
Neisseria Gonorrhoeae ◽  
Reproductive Tract ◽  
Public Health Problem ◽  
Cell Types ◽  
Asymptomatic Infection ◽  
Female Reproductive Tract ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
Host Cell Signaling

Gonorrhea, caused by Neisseria gonorrhoeae, is a common sexually transmitted infection and an urgent public health problem. Humans are the exclusive host, and the genital tract with heterogeneous epithelia is the primary niche of this bacterium, creating unique challenges for understanding its pathogenesis. The cervical tissue explant model that we have developed enabled us to show that the properties of the epithelial cells in the female reproductive tract are the main factors driving gonococcal adaptation. Gonococcal variants that colonize strongly and penetrate poorly, thereby causing asymptomatic infection, survive better in the cervix. Gonococci adapt to different epithelial cell types by varying their surfaces and modulating distinct epithelial cell-cell adhesion complexes through manipulation of host cell signaling. These findings provide critical new insights on the mechanisms by which N. gonorrhoeae adapts to the human mucosal surface and causes asymptomatic infection.

scholarly journals MetQ of Neisseria gonorrhoeae Is a Surface-Expressed Antigen That Elicits Bactericidal and Functional Blocking Antibodies

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Evgeny A. Semchenko ◽  
Christopher J. Day ◽  
Kate L. Seib
Keyword(s):  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Bacterial Surface ◽  
Functional Blocking ◽  
Blocking Antibodies ◽  
Candidate Antigen

ABSTRACT Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection (STI) gonorrhea, is a growing public health threat for which a vaccine is urgently needed. We characterized the functional role of the gonococcal MetQ protein, which is the methionine binding component of an ABC transporter system, and assessed its potential as a candidate antigen for inclusion in a gonococcal vaccine. MetQ has been found to be highly conserved in all strains investigated to date, it is localized on the bacterial surface, and it binds l-methionine with a high affinity. MetQ is also involved in gonococcal adherence to cervical epithelial cells. Mutants lacking MetQ have impaired survival in human monocytes, macrophages, and serum. Furthermore, antibodies raised against MetQ are bactericidal and are able to block gonococcal adherence to epithelial cells. These data suggest that MetQ elicits both bactericidal and functional blocking antibodies and is a valid candidate antigen for additional investigation and possible inclusion in a vaccine for prevention of gonorrhea.

scholarly journals Neisseria gonorrhoeae Metalloprotease NGO1686 Is Required for Full Piliation, and Piliation Is Required for Resistance to H2O2- and Neutrophil-Mediated Killing

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Elizabeth A. Stohl ◽  
Erin M. Dale ◽  
Alison K. Criss ◽  
H. Steven Seifert
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Virulence Factor ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Type Iv ◽  
Specific Pathogen ◽  
Associated Functions ◽  
Host Tissues ◽  
Human Specific

ABSTRACTThe sexually transmitted infection gonorrhea is caused exclusively by the human-specific pathogenNeisseria gonorrhoeae. Type IV pili are an essential virulence factor uniformly expressed on clinical gonococcal isolates and are required for several aspects of gonococcal pathogenesis, including adherence to host tissues, autoagglutination, twitching motility, and the uptake of DNA during transformation. Symptomatic gonococcal infection is characterized by the influx of neutrophils or polymorphonuclear leukocytes (PMNs) to the site of infection. PMNs are a key component of gonococcal pathogenesis, mediating the innate immune response through the use of oxidative and nonoxidative killing mechanisms. The M23B family zinc metallopeptidase NGO1686 is required for gonococci to survive oxidative killing by H2O2- and PMN-mediated killing through unknown mechanisms, but the only known target of NGO1686 is peptidoglycan. We report that the effect of NGO1686 on survival after exposure to H2O2and PMNs is mediated through its role in elaborating pili and that nonpiliated mutants ofN. gonorrhoeaeare less resistant to killing by H2O2, LL-37, and PMNs than the corresponding piliated strains. These findings add to the various virulence-associated functions attributable to gonococcal pili and may explain the selection basis for piliation in clinical isolates ofN. gonorrhoeae.IMPORTANCESuccessful infectious agents need to overcome host defense systems to establish infection. We show that theNeisseriapilus, a major virulence factor of this organism, which causes gonorrhea, helps protect the bacterium from two major killing mechanisms used by the host to combat infections. We also show that to express the pilus, an enzyme needs to partially degrade the cell wall of the bacterium.

scholarly journals Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Benjamin I. Baarda ◽  
Ryszard A. Zielke ◽  
Alaina K. Holm ◽  
Aleksandra E. Sikora
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Vaccine Development ◽  
Phylogenetic Analyses ◽  
Low Frequency ◽  
Surface Proteins ◽  
Effective Vaccine ◽  
High Morbidity ◽  
Transmitted Infection ◽  
Content Type ◽  
Vaccine Candidates

ABSTRACT A protective vaccine is the only viable way to stop the spread of gonorrhea in the face of rising antibiotic resistance. However, the notorious phase and antigenic variation of Neisseria gonorrhoeae surface proteins remains one of the challenges in vaccine development. To facilitate vaccine advancement efforts, we carried out comprehensive bioinformatic analyses of sequence variation by comparing 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates deposited in the Neisseria PubMLST database. Eight protein antigens showed exceptional conservation by having a single allele variant distributed in >80% of isolates. An additional 18 vaccine candidates were represented by ≤3 alleles in >50% of N. gonorrhoeae isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between N. gonorrhoeae and N. meningitidis. Up to 44% of N. meningitidis alleles for both antigens have premature stop codons, suggesting differential expression. Mapping polymorphisms to the available three-dimensional structures of 12 antigens revealed low-frequency surface polymorphisms. PorB and TbpB possessed numerous high-prevalence polymorphic sites. While TbpA was also highly variable, conserved loops were nonetheless identified. A high degree of sequence conservation, the distribution of a single antigen variant among N. gonorrhoeae strains globally, or low-frequency sequence polymorphisms in surface loops make ACP, AniA, BamA, BamE, MtrE, NspA, NGO0778, NGO1251, NGO1985, OpcA, PldA, Slam2, and ZnuD promising candidates for a gonorrhea vaccine. Finally, the commonly used N. gonorrhoeae FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants. IMPORTANCE Neisseria gonorrhoeae, the Gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. N. gonorrhoeae’s “superbug” status, its high morbidity, and the serious health impact associated with gonorrhea highlight the importance of vaccine development. One of the longstanding barriers to developing an effective vaccine against N. gonorrhoeae is the remarkable variability of surface-exposed antigens. In this report, we addressed this roadblock by applying extensive bioinformatic analyses to 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates. Our studies are important, as they reveal promising, conserved gonorrhea vaccine candidates and aid structural vaccinology. Moreover, these approaches are broadly applicable to other infectious diseases where surface antigen variability impedes successful vaccine design.

scholarly journals Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2

2015 ◽  
Vol 83 (9) ◽  
pp. 3410-3417 ◽  
Author(s):  
Kathleen Nudel ◽  
Paola Massari ◽  
Caroline A. Genco
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Cell Types ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Cell Death Pathways ◽  
Host Cell Death ◽  
Cervical Epithelial Cells

Several bacterial pathogens persist and survive in the host by modulating host cell death pathways. We previously demonstrated thatNeisseria gonorrhoeae, a Gram-negative pathogen responsible for the sexually transmitted infection gonorrhea, protects against exogenous induction of apoptosis in human cervical epithelial cells. However, induction of cell death byN. gonorrhoeaehas also been reported in other cell types. The mechanisms by whichN. gonorrhoeaemodulates cell death are not clear, although a role for the inhibitor of apoptosis-2 (cIAP2) has been proposed. In this study, we confirmed thatN. gonorrhoeaeinduces production of cIAP2 in human cervical epithelial cells. High levels of intracellular cIAP2 were detected early afterN. gonorrhoeaestimulation, which was followed by a marked decrease at 24 h. At this time point, we observed increased levels of extracellular cIAP2 associated with exosomes and an overall increase in production of exosomes. Inhibition of cIAP2 inN. gonorrhoeae-stimulated epithelial cells resulted in increased cell death and interleukin-1β (IL-1β) production. Collectively these results indicate thatN. gonorrhoeaestimulation of human endocervical epithelial cells induces the release of cIAP2, an essential regulator of cell death and immune signaling.

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