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The novel interaction between Neisseria gonorrhoeae TdfJ and human S100A7 allows gonococci to subvert host zinc restriction.
Maurakis S, Keller K, Maxwell CN, Pereira K, Chazin WJ, Criss AK, Cornelissen CN
(2019) PLoS Pathog 15: e1007937
MeSH Terms: Amino Acid Sequence, Animals, Bacterial Outer Membrane Proteins, Gonorrhea, Host-Pathogen Interactions, Humans, Mice, Neisseria gonorrhoeae, S100 Calcium Binding Protein A7, Zinc
Show Abstract · Added March 11, 2020
Neisseria gonorrhoeae causes the sexually-transmitted infection gonorrhea, a global disease that is difficult to treat and for which there is no vaccine. This pathogen employs an arsenal of conserved outer membrane proteins called TonB-dependent transporters (TdTs) that allow the gonococcus to overcome nutritional immunity, the host strategy of sequestering essential nutrients away from invading bacteria to handicap infectious ability. N. gonorrhoeae produces eight known TdTs, of which four are utilized for acquisition of iron or iron chelates from host-derived proteins or xenosiderophores produced by other bacteria. Of the remaining TdTs, two of them, TdfH and TdfJ, facilitate zinc uptake. TdfH was recently shown to bind Calprotectin, a member of the S100 protein family, and subsequently extract its zinc, which is then internalized by N. gonorrhoeae. Like Calprotectin, other S100s are also capable of binding transition metals such as zinc and copper, and thus have demonstrated growth suppression of numerous other pathogens via metal sequestration. Considering the functional and structural similarities of the TdTs and of the S100s, as well as the upregulation in response to Zn limitation shown by TdfH and TdfJ, we sought to evaluate whether other S100s have the ability to support gonococcal growth by means of zinc acquisition and to frame this growth in the context of the TdTs. We found that both S100A7 and S10012 are utilized by N. gonorrhoeae as a zinc source in a mechanism that depends on the zinc transport system ZnuABC. Moreover, TdfJ binds directly to S100A7, from which it internalizes zinc. This interaction is restricted to the human version of S100A7, and zinc presence in S100A7 is required to fully support gonococcal growth. These studies highlight how gonococci co-opt human nutritional immunity, by presenting a novel interaction between TdfJ and human S100A7 for overcoming host zinc restriction.
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MeSH Terms
Evidence of Fe3+ interaction with the plug domain of the outer membrane transferrin receptor protein of Neisseria gonorrhoeae: implications for Fe transport.
Banerjee S, Siburt CJ, Mistry S, Noto JM, DeArmond P, Fitzgerald MC, Lambert LA, Cornelissen CN, Crumbliss AL
(2012) Metallomics 4: 361-72
MeSH Terms: Amino Acid Sequence, Bacterial Outer Membrane Proteins, Binding Sites, Biological Transport, Circular Dichroism, Gonorrhea, Humans, Hydrogen-Ion Concentration, Iron, Models, Molecular, Molecular Sequence Data, Mutation, Neisseria gonorrhoeae, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins, Sequence Homology, Amino Acid, Spectrometry, Fluorescence, Transferrin, Transferrin-Binding Protein A
Show Abstract · Added April 25, 2016
Neisseria gonorrhoeae is an obligate pathogen that hijacks iron from the human iron transport protein, holo-transferrin (Fe(2)-Tf), by expressing TonB-dependent outer membrane receptor proteins, TbpA and TbpB. Homologous to other TonB-dependent outer membrane transporters, TbpA is thought to consist of a β-barrel with an N-terminal plug domain. Previous reports by our laboratories show that the sequence EIEYE in the plug domain is highly conserved among various bacterial species that express TbpA and plays a crucial role in iron utilization for gonococci. We hypothesize that this highly conserved EIEYE sequence in the TbpA plug, rich in hard oxygen donor groups, binds with Fe(3+) through the transport process across the outer membrane through the β-barrel. Sequestration of Fe(3+) by the TbpA-plug supports the paradigm that the ferric iron must always remain chelated and controlled throughout the transport process. In order to test this hypothesis here we describe the ability of both the recombinant wild-type plug, and three small peptides that encompass the sequence EIEYE of the plug, to bind Fe(3+). This is the first report of the expression/isolation of the recombinant wild-type TbpA plug. Although CD and SUPREX spectroscopies suggest that a non-native structure is observed for the recombinant plug, fluorescence quenching titrations indicate that the wild-type recombinant TbpA plug binds Fe (3+) with a conditional log K(d) = 7 at pH 7.5, with no evidence of binding at pH 6.3. A recombinant TbpA plug with mutated sequence (NEIEYEN → NEIAAAN) shows no evidence of Fe(3+) binding under our experimental set up. Interestingly, in silico modeling with the wild-type plug also predicts a flexible loop structure for the EIEYE sequence under native conditions which once again supports the Fe(3+) binding hypothesis. These in vitro observations are consistent with the hypothesis that the EIEYE sequence in the wild-type TbpA plug binds Fe(3+) during the outer membrane transport process in vivo.
This journal is © The Royal Society of Chemistry 2012
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20 MeSH Terms
Hijacking transferrin bound iron: protein-receptor interactions involved in iron transport in N. gonorrhoeae.
Siburt CJ, Roulhac PL, Weaver KD, Noto JM, Mietzner TA, Cornelissen CN, Fitzgerald MC, Crumbliss AL
(2009) Metallomics 1: 249-55
MeSH Terms: Humans, Iron, Neisseria gonorrhoeae, Transferrin, Transferrin-Binding Protein A, Transferrin-Binding Protein B
Show Abstract · Added April 25, 2016
Neisseria gonorrhoeae has the capacity to acquire iron from its human host by removing this essential nutrient from serum transferrin. The transferrin binding proteins, TbpA and TbpB constitute the outer membrane receptor complex responsible for binding transferrin, extracting the tightly bound iron from the host-derived molecule, and transporting iron into the periplasmic space of this Gram-negative bacterium. Once iron is transported across the outer membrane, ferric binding protein A (FbpA) moves the iron across the periplasmic space and initiates the process of transport into the bacterial cytosol. The results of the studies reported here define the multiple steps in the iron transport process in which TbpA and TbpB participate. Using the SUPREX technique for assessing the thermodynamic stability of protein-ligand complexes, we report herein the first direct measurement of periplasmic FbpA binding to the outer membrane protein TbpA. We also show that TbpA discriminates between apo- and holo-FbpA; i.e. the TbpA interaction with apo-FbpA is higher affinity than the TbpA interaction with holo-FbpA. Further, we demonstrate that both TbpA and TbpB individually can deferrate transferrin and ferrate FbpA without energy supplied from TonB resulting in sequestration by apo-FbpA.
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6 MeSH Terms
Identification of TbpA residues required for transferrin-iron utilization by Neisseria gonorrhoeae.
Noto JM, Cornelissen CN
(2008) Infect Immun 76: 1960-9
MeSH Terms: Amino Acid Sequence, Amino Acid Substitution, Bacterial Proteins, Iron, Molecular Sequence Data, Mutagenesis, Site-Directed, Neisseria gonorrhoeae, Protein Binding, Protein Structure, Tertiary, Sequence Alignment, Transferrin, Transferrin-Binding Protein A
Show Abstract · Added April 25, 2016
Neisseria gonorrhoeae requires iron for survival in the human host and therefore expresses high-affinity receptors for iron acquisition from host iron-binding proteins. The gonococcal transferrin-iron uptake system is composed of two transferrin binding proteins, TbpA and TbpB. TbpA is a TonB-dependent, outer membrane transporter critical for iron acquisition, while TbpB is a surface-exposed lipoprotein that increases the efficiency of iron uptake. The precise mechanism by which TbpA mediates iron acquisition has not been elucidated; however, the process is distinct from those of characterized siderophore transporters. Similar to these TonB-dependent transporters, TbpA is proposed to have two distinct domains, a beta-barrel and a plug domain. We hypothesize that the TbpA plug coordinates iron and therefore potentially functions in multiple steps of transferrin-mediated iron acquisition. To test this hypothesis, we targeted a conserved motif within the TbpA plug domain and generated single, double, and triple alanine substitution mutants. Mutagenized TbpAs were expressed on the gonococcal cell surface and maintained wild-type transferrin binding affinity. Single alanine substitution mutants internalized iron at wild-type levels, while the double and triple mutants showed a significant decrease in iron uptake. Moreover, the triple alanine substitution mutant was unable to grow on transferrin as a sole iron source; however, expression of TbpB compensated for this defect. These data indicate that the conserved motif between residues 120 and 122 of the TbpA plug domain is critical for transferrin-iron utilization, suggesting that this region plays a role in iron acquisition that is shared by both TbpA and TbpB.
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12 MeSH Terms
Antimicrobial resistance among Neisseria gonorrhoeae isolates from Ulaanbaatar, Mongolia.
Schwebke JR, Vermund SH
(2001) Sex Transm Infect 77: 463
MeSH Terms: Drug Resistance, Bacterial, Humans, Microbial Sensitivity Tests, Neisseria gonorrhoeae
Added March 5, 2014
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Prevalence of gonococcal and chlamydial infections in commercial sex workers in a Peruvian Amazon city.
Paris M, Gotuzzo E, Goyzueta G, Aramburu J, Caceres CF, Castellano T, Jordan NN, Vermund SH, Hook EW
(1999) Sex Transm Dis 26: 103-7
MeSH Terms: Adolescent, Adult, Chlamydia Infections, Chlamydia trachomatis, Condoms, Female, Gonorrhea, Humans, Neisseria gonorrhoeae, Odds Ratio, Peru, Pilot Projects, Prevalence, Risk Assessment, Sex Work, Urine
Show Abstract · Added March 5, 2014
BACKGROUND - Iquitos Peru, a densely populated port city housing both a large military base and a booming tourist industry, provides a thriving market for commercial sex and, consequently, sexually transmitted disease (STD). The purpose of this study was to characterize the prevalence of gonococcal and chlamydial infections among commercial sex workers (CSWs) and to correlate those findings with social/behavioral characteristics.
METHODS - One hundred CSWs, recruited through street and brothel outreach, were administered questionnaires. Urine specimens were collected for gonorrhea and chlamydia testing using ligase chain reaction assays.
RESULTS - Twenty-eight percent of CSWs were positive for chlamydia (22%) or gonorrhea (14%). Registered CSWs were more likely to have worked more than 5 years (p = 0.03), report 10 or more partners (p = 0.002), and work in brothels (p < 0.001). Significant associations were also noted between infection status and age, with adolescents at increased risk (odds ratio [OR] = 4.13, p = 0.001), and duration of employment, with those employed less than 5 years at increased risk (OR = 3.72, p = 0.04). The latter association, however, was because of age. Also, most CSWs believed themselves to be at no/small risk or didn't know their risk of future gonococcal infection (30%/12% and 25%, respectively) and AIDS (25%/8% and 35%, respectively), with 11% perceiving AIDS as more of a threat.
CONCLUSIONS - High infection rates, lack of knowledge regarding STD/HIV risk assessment, and other high-risk behavior prevalent among this population stress the need for STD intervention. The study further suggests that educational/risk assessment programs and risk reduction interventions could be successful.
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16 MeSH Terms
Ligation of cell surface heparan sulfate proteoglycans by antibody-coated beads stimulates phagocytic uptake into epithelial cells: a model for cellular invasion by Neisseria gonorrhoeae.
Dehio C, Freissler E, Lanz C, Gómez-Duarte OG, David G, Meyer TF
(1998) Exp Cell Res 242: 528-39
MeSH Terms: Actins, Antibodies, Bacterial, Antibodies, Monoclonal, Antigens, Bacterial, Bacterial Adhesion, Biopolymers, Cross-Linking Reagents, Endocytosis, Enzyme Inhibitors, Epithelial Cells, HeLa Cells, Heparan Sulfate Proteoglycans, Humans, Ligands, Microspheres, Neisseria gonorrhoeae, Phagocytosis, Protein Kinase C, Receptors, Cell Surface, Sensitivity and Specificity, Tumor Cells, Cultured, Vitronectin
Show Abstract · Added May 27, 2014
Binding of a particular opacity outer membrane protein (Opa) of Neisseria gonorrhoeae to cell surface heparan sulfate proteoglycans (HSPGs) of epithelial cells results in tight bacterial adherence; however, the role of this ligand-receptor interaction in triggering the subsequent bacterial internalization step is uncertain. Here we have used latex beads coated with HSPG-ligating antibodies as an in vitro model to study the role of HSPGs in gonococcal uptake into epithelial cells. Beads and gonococci showed the same cell line-specified adherence patterns and increase in phagocytic uptake mediated by serum or purified vitronectin (Vn). Heparitinase digestion as well as antibody competition experiments indicate that a critical level of HSPG ligation is necessary and sufficient to trigger phagocytic uptake into epithelial cells. Vn was found to specifically enhance HSPG-dependent phagocytic uptake while phagocytosis resulting from the ligation of other cell surface receptors was unaffected in the presence of Vn. Pharmacological studies with PKC inhibitors suggest a role for PKC in phagocytic uptake of HSPG-ligating beads. The use of drugs impairing cytoskeletal functions indicates that HSPG-dependent phagocytosis requires actin polymerization by a process distinct from receptor-mediated endocytosis.
Copyright 1998 Academic Press.
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22 MeSH Terms
Vitronectin-dependent invasion of epithelial cells by Neisseria gonorrhoeae involves alpha(v) integrin receptors.
Dehio M, Gómez-Duarte OG, Dehio C, Meyer TF
(1998) FEBS Lett 424: 84-8
MeSH Terms: Antigens, Bacterial, Bacterial Adhesion, Bacterial Proteins, Epithelial Cells, HeLa Cells, Humans, Neisseria gonorrhoeae, Peptides, Protein Kinase C, Receptors, Fibronectin, Tumor Cells, Cultured, Vitronectin
Show Abstract · Added May 27, 2014
Binding of vitronectin (VN) to Neisseria gonorrhoeae expressing the heparan sulfate proteoglycan (HSPG) specific Opa50 protein was recently shown to trigger bacterial internalization into distinct epithelial cell lines. We have investigated the role of VN-binding integrin receptors and protein kinase C (PKC) in VN-triggered bacterial uptake. Blocking integrin function by RGDS peptides or by antibodies specific to alpha(v)beta5 or alpha(v)beta3 resulted in an abrogation of VN-triggered bacterial internalization. Moreover, inhibitors of PKC were found to block VN-triggered uptake. The essential role of alpha(v) integrins and the presumable involvement of PKC in VN-triggered gonococcal uptake are discussed.
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12 MeSH Terms
Binding of vitronectin to opa-expressing Neisseria gonorrhoeae mediates invasion of HeLa cells.
Gómez-Duarte OG, Dehio M, Guzmán CA, Chhatwal GS, Dehio C, Meyer TF
(1997) Infect Immun 65: 3857-66
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Adhesion, Blood, Cattle, Epithelium, Fibrinogen, Fibronectins, HeLa Cells, Humans, Laminin, Microscopy, Confocal, Neisseria gonorrhoeae, Time Factors, Vitronectin
Show Abstract · Added May 27, 2014
Neisseria gonorrhoeae induces local infections in the human genitourinary tract and can disseminate to other organs to cause severe disease. Blood-derived factors present in the genital mucosa have been suggested to facilitate the spread of N. gonorrhoeae in disseminated gonococcal infections. Using gentamicin invasion assays and confocal microscopy, we observed a strong stimulatory effect of fetal calf serum (FCS) on the gonococcal invasion of HeLa cells. FCS-mediated invasion was dependent on the expression of the epithelial cell invasion-associated Opa protein (plasmid-encoded Opa50 or its chromosomal homolog Opa30), while N. gonorrhoeae expressing noninvasive Opa proteins (Opa(51-60)) or no Opa protein (Opa-) was not invasive even in the presence of FCS. Incubation of N. gonorrhoeae MS11 with biotinylated FCS revealed a 78-kDa protein as the prominent protein binding to Opa50- or Opa30-expressing gonococci. This protein was recognized by antibodies against vitronectin (VN) in Western blots. Purified human or bovine VN efficiently bound to Opa50-expressing gonococci, while binding to noninvasive Opa- or Opa52-expressing gonococci was significantly lower. Binding of VN was inhibited by heparin in a concentration-dependent manner, indicating that the heparin binding sites present in VN or Opa50 may play an essential role in this interaction. Based on gentamicin invasion assays and confocal microscopy studies, VN binding was associated with an increased invasion of Opa50- and Opa30-expressing gonococci into HeLa cells. The ability of VN to mediate entry into epithelial cells may constitute an important event in the pathogenesis of local as well as disseminated gonococcal infections.
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15 MeSH Terms