skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women

Abstract

ABSTRACT Neisseria gonorrhoeaeis a bacterial pathogen responsible for the sexually transmitted infection gonorrhea. Emergence of antimicrobial resistance (AMR) ofN. gonorrhoeaeworldwide has resulted in limited therapeutic choices for this infection. Men who seek treatment often have symptomatic urethritis; in contrast, gonococcal cervicitis in women is usually minimally symptomatic, but may progress to pelvic inflammatory disease. Previously, we reported the first analysis of gonococcal transcriptome expression determined in secretions from women with cervical infection. Here, we defined gonococcal global transcriptional responses in urethral specimens from men with symptomatic urethritis and compared these with transcriptional responses in specimens obtained from women with cervical infections andin vitro-grownN. gonorrhoeaeisolates. This is the first comprehensive comparison of gonococcal gene expression in infected men and women. RNA sequencing analysis revealed that 9.4% of gonococcal genes showed increased expression exclusively in men and included genes involved in host immune cell interactions, while 4.3% showed increased expression exclusively in women and included phage-associated genes. Infected men and women displayed comparable antibiotic-resistant genotypes andin vitrophenotypes, but a 4-fold higher expression of the Mtr efflux pump-related genes was observed in men. These results suggest that expression of AMR genes is programed genotypically and also driven by sex-specific environments. Collectively, our results indicate thatmore » distinctN. gonorrhoeaegene expression signatures are detected during genital infection in men and women. We propose that therapeutic strategies could target sex-specific differences in expression of antibiotic resistance genes. IMPORTANCERecent emergence of antimicrobial resistance ofNeisseria gonorrhoeaeworldwide has resulted in limited therapeutic choices for treatment of infections caused by this organism. We performed global transcriptomic analysis ofN. gonorrhoeaein subjects with gonorrhea who attended a Nanjing, China, sexually transmitted infection (STI) clinic, where antimicrobial resistance ofN. gonorrhoeaeis high and increasing. We found thatN. gonorrhoeaetranscriptional responses to infection differed in genital specimens taken from men and women, particularly antibiotic resistance gene expression, which was increased in men. These sex-specific findings may provide a new approach to guide therapeutic interventions and preventive measures that are also sex specific while providing additional insight to address antimicrobial resistance ofN. gonorrhoeae.« less

Authors:
ORCiD logo; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1503578
Report Number(s):
PNNL-SA-138245
Journal ID: ISSN 2379-5042
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
mSphere
Additional Journal Information:
Journal Volume: 3; Journal Issue: 3; Journal ID: ISSN 2379-5042
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
RNA-seq, human mucosal infection, neisseria gonorrhoeae, antibiotic resistance

Citation Formats

Nudel, Kathleen, McClure, Ryan, Moreau, Matthew, Briars, Emma, Abrams, A. Jeanine, Tjaden, Brian, Su, Xiao-Hong, Trees, David, Rice, Peter A., Massari, Paola, Genco, Caroline A., and D'Orazio, Sarah E. F. Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women. United States: N. p., 2018. Web. doi:10.1128/mSphereDirect.00312-18.
Nudel, Kathleen, McClure, Ryan, Moreau, Matthew, Briars, Emma, Abrams, A. Jeanine, Tjaden, Brian, Su, Xiao-Hong, Trees, David, Rice, Peter A., Massari, Paola, Genco, Caroline A., & D'Orazio, Sarah E. F. Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women. United States. doi:10.1128/mSphereDirect.00312-18.
Nudel, Kathleen, McClure, Ryan, Moreau, Matthew, Briars, Emma, Abrams, A. Jeanine, Tjaden, Brian, Su, Xiao-Hong, Trees, David, Rice, Peter A., Massari, Paola, Genco, Caroline A., and D'Orazio, Sarah E. F. Wed . "Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women". United States. doi:10.1128/mSphereDirect.00312-18.
@article{osti_1503578,
title = {Transcriptome Analysis of Neisseria gonorrhoeae during Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants between Men and Women},
author = {Nudel, Kathleen and McClure, Ryan and Moreau, Matthew and Briars, Emma and Abrams, A. Jeanine and Tjaden, Brian and Su, Xiao-Hong and Trees, David and Rice, Peter A. and Massari, Paola and Genco, Caroline A. and D'Orazio, Sarah E. F.},
abstractNote = {ABSTRACT Neisseria gonorrhoeaeis a bacterial pathogen responsible for the sexually transmitted infection gonorrhea. Emergence of antimicrobial resistance (AMR) ofN. gonorrhoeaeworldwide has resulted in limited therapeutic choices for this infection. Men who seek treatment often have symptomatic urethritis; in contrast, gonococcal cervicitis in women is usually minimally symptomatic, but may progress to pelvic inflammatory disease. Previously, we reported the first analysis of gonococcal transcriptome expression determined in secretions from women with cervical infection. Here, we defined gonococcal global transcriptional responses in urethral specimens from men with symptomatic urethritis and compared these with transcriptional responses in specimens obtained from women with cervical infections andin vitro-grownN. gonorrhoeaeisolates. This is the first comprehensive comparison of gonococcal gene expression in infected men and women. RNA sequencing analysis revealed that 9.4% of gonococcal genes showed increased expression exclusively in men and included genes involved in host immune cell interactions, while 4.3% showed increased expression exclusively in women and included phage-associated genes. Infected men and women displayed comparable antibiotic-resistant genotypes andin vitrophenotypes, but a 4-fold higher expression of the Mtr efflux pump-related genes was observed in men. These results suggest that expression of AMR genes is programed genotypically and also driven by sex-specific environments. Collectively, our results indicate that distinctN. gonorrhoeaegene expression signatures are detected during genital infection in men and women. We propose that therapeutic strategies could target sex-specific differences in expression of antibiotic resistance genes. IMPORTANCERecent emergence of antimicrobial resistance ofNeisseria gonorrhoeaeworldwide has resulted in limited therapeutic choices for treatment of infections caused by this organism. We performed global transcriptomic analysis ofN. gonorrhoeaein subjects with gonorrhea who attended a Nanjing, China, sexually transmitted infection (STI) clinic, where antimicrobial resistance ofN. gonorrhoeaeis high and increasing. We found thatN. gonorrhoeaetranscriptional responses to infection differed in genital specimens taken from men and women, particularly antibiotic resistance gene expression, which was increased in men. These sex-specific findings may provide a new approach to guide therapeutic interventions and preventive measures that are also sex specific while providing additional insight to address antimicrobial resistance ofN. gonorrhoeae.},
doi = {10.1128/mSphereDirect.00312-18},
journal = {mSphere},
issn = {2379-5042},
number = 3,
volume = 3,
place = {United States},
year = {2018},
month = {6}
}

Works referenced in this record:

Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000–2013
journal, September 2016

  • Grad, Yonatan H.; Harris, Simon R.; Kirkcaldy, Robert D.
  • Journal of Infectious Diseases, Vol. 214, Issue 10
  • DOI: 10.1093/infdis/jiw420

Characterization of the dsDNA prophage sequences in the genome of Neisseria gonorrhoeae and visualization of productive bacteriophage
journal, January 2007

  • Piekarowicz, Andrzej; Kłyż, Aneta; Majchrzak, Michał
  • BMC Microbiology, Vol. 7, Issue 1
  • DOI: 10.1186/1471-2180-7-66

Gonorrhoea in men: clinical and diagnostic aspects.
journal, December 1996

  • Sherrard, J.; Barlow, D.
  • Sexually Transmitted Infections, Vol. 72, Issue 6
  • DOI: 10.1136/sti.72.6.422

Macrolide treatment failure in a case of secondary syphilis: a novel A2059G mutation in the 23S rRNA gene of Treponema pallidum subsp. pallidum
journal, May 2009

  • Matejkova, P.; Flasarova, M.; Zakoucka, H.
  • Journal of Medical Microbiology, Vol. 58, Issue 6
  • DOI: 10.1099/jmm.0.007542-0

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae: A Major Global Public Health Problem in the 21st Century
journal, June 2016


A gonococcal porA pseudogene: implications for understanding the evolution and pathogenicity of Neisseria gonorrhoeae
journal, November 1998


Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914)
journal, October 2015

  • Su, Xiao-Hong; Wang, Bao-Xi; Le, Wen-Jing
  • Antimicrobial Agents and Chemotherapy, Vol. 60, Issue 1
  • DOI: 10.1128/AAC.01211-15

Spermine impairs biofilm formation by Neisseria gonorrhoeae
journal, April 2013

  • Goytia, Maira; Dhulipala, Vijaya L.; Shafer, William M.
  • FEMS Microbiology Letters, Vol. 343, Issue 1
  • DOI: 10.1111/1574-6968.12130

Nonhybrid, finished microbial genome assemblies from long-read SMRT sequencing data
journal, May 2013

  • Chin, Chen-Shan; Alexander, David H.; Marks, Patrick
  • Nature Methods, Vol. 10, Issue 6
  • DOI: 10.1038/nmeth.2474

Iron-regulated small RNA expression as Neisseria gonorrhoeae FA 1090 transitions into stationary phase growth
journal, April 2017


A Gonococcal Efflux Pump System Enhances Bacterial Survival in a Female Mouse Model of Genital Tract Infection
journal, September 2003


Lipid A’s Structure Mediates Neisseria gonorrhoeae Fitness during Experimental Infection of Mice and Men
journal, November 2013

  • Hobbs, Marcia M.; Anderson, James E.; Balthazar, Jacqueline T.
  • mBio, Vol. 4, Issue 6
  • DOI: 10.1128/mBio.00892-13

Gonococcal Cervicitis: A Role for Biofilm in Pathogenesis
journal, December 2008

  • Steichen, Christopher T.; Shao, Jian Q.; Ketterer, Margaret R.
  • The Journal of Infectious Diseases, Vol. 198, Issue 12
  • DOI: 10.1086/593336

Asymptomatic Gonorrhea in Men: Diagnosis, Natural Course, Prevalence and Significance
journal, January 1974

  • Handsfield, H. Hunter; Lipman, Timothy O.; Harnisch, James P.
  • New England Journal of Medicine, Vol. 290, Issue 3
  • DOI: 10.1056/NEJM197401172900301

Molecular and catalytic properties of a peroxiredoxin-glutaredoxin hybrid from Neisseria meningitidis
journal, October 2003


The Gonococcal Fur-Regulated tbpA and tbpB Genes Are Expressed during Natural Mucosal Gonococcal Infection
journal, June 2005


The Composition and Metabolic Phenotype of Neisseria gonorrhoeae Biofilms
journal, January 2011

  • Falsetta, Megan L.; Steichen, Christopher T.; McEwan, Alastair G.
  • Frontiers in Microbiology, Vol. 2
  • DOI: 10.3389/fmicb.2011.00075

Biofilm Formation by Neisseria gonorrhoeae
journal, March 2005


Deep sequencing-based analysis of the anaerobic stimulon in Neisseria gonorrhoeae
journal, January 2011


The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers
journal, February 1998


Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action
journal, July 2017


Computational analysis of bacterial RNA-Seq data
journal, May 2013

  • McClure, Ryan; Balasubramanian, Divya; Sun, Yan
  • Nucleic Acids Research, Vol. 41, Issue 14
  • DOI: 10.1093/nar/gkt444

The role of complement receptor 3 (CR3) in Neisseria gonorrhoeae infection of human cervical epithelia
journal, September 2001


The Gonococcal Transcriptome during Infection of the Lower Genital Tract in Women
journal, August 2015


The role of acidification in the inhibition of Neisseria gonorrhoeae by vaginal lactobacilli during anaerobic growth
journal, January 2011

  • Graver, Michelle A.; Wade, Jeremy J.
  • Annals of Clinical Microbiology and Antimicrobials, Vol. 10, Issue 1
  • DOI: 10.1186/1476-0711-10-8

Population Mobility, Globalization, and Antimicrobial Drug Resistance
journal, January 2009


Defenses against Oxidative Stress in Neisseria gonorrhoeae: a System Tailored for a Challenging Environment
journal, June 2006

  • Seib, K. L.; Wu, H. -J.; Kidd, S. P.
  • Microbiology and Molecular Biology Reviews, Vol. 70, Issue 2
  • DOI: 10.1128/MMBR.00044-05

Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among Men with Urethritis and Their Female Sex Partners
journal, December 1998

  • Lin, Juey‐Shin L.; Donegan, S. Patrick; Heeren, Timothy C.
  • The Journal of Infectious Diseases, Vol. 178, Issue 6
  • DOI: 10.1086/314485

A co-operative interaction between Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary cervical epithelial cells
journal, September 2002


The Pathobiology of Neisseria gonorrhoeae Lower Female Genital Tract Infection
journal, January 2011


kSNP3.0: SNP detection and phylogenetic analysis of genomes without genome alignment or reference genome: Table 1
journal, April 2015


The Iron-Repressed, AraC-Like Regulator MpeR Activates Expression of fetA in Neisseria gonorrhoeae
journal, September 2011

  • Hollander, Aimee; Mercante, Alexandra Dubon; Shafer, William M.
  • Infection and Immunity, Vol. 79, Issue 12
  • DOI: 10.1128/IAI.05806-11

Transcriptional control of the mtr efflux system of Neisseria gonorrhoeae.
journal, July 1995


Growth phase-dependent regulation of nuoA-N expression in Escherichia coli K-12 by the Fis protein: upstream binding sites and bioenergetic significance
journal, December 1999

  • Wackwitz, B.; Bongaerts, J.; Goodman, S. D.
  • Molecular and General Genetics MGG, Vol. 262, Issue 4-5
  • DOI: 10.1007/s004380051153

Diffusion of Antibiotics through the PilQ Secretin in Neisseria gonorrhoeae Occurs through the Immature, Sodium Dodecyl Sulfate-Labile Form
journal, January 2015

  • Nandi, Sobhan; Swanson, Shauna; Tomberg, Joshua
  • Journal of Bacteriology, Vol. 197, Issue 8
  • DOI: 10.1128/JB.02628-14

Neisseria gonorrhoeae host adaptation and pathogenesis
journal, February 2018


Microbiologic aerobic studies on normal male urethra
journal, August 2000


Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae
journal, September 2015

  • Cash, Devin R.; Noinaj, Nicholas; Buchanan, Susan K.
  • Infection and Immunity, Vol. 83, Issue 11
  • DOI: 10.1128/IAI.00762-15

Vaginal microbiome of reproductive-age women
journal, June 2010

  • Ravel, J.; Gajer, P.; Abdo, Z.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue Supplement_1
  • DOI: 10.1073/pnas.1002611107

Neisseria Prophage Repressor Implicated in Gonococcal Pathogenesis
journal, July 2013

  • Daou, Nadine; Yu, Chunxiao; Mcclure, Ryan
  • Infection and Immunity, Vol. 81, Issue 10
  • DOI: 10.1128/IAI.00298-13

Relation between Genetic Markers of Drug Resistance and Susceptibility Profile of Clinical Neisseria gonorrhoeae Strains
journal, March 2008

  • Ilina, E. N.; Vereshchagin, V. A.; Borovskaya, A. D.
  • Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 6
  • DOI: 10.1128/AAC.01420-07

The Molecular Mechanisms Used by Neisseria gonorrhoeae To Initiate Infection Differ between Men and Women
journal, October 2004


Vaginal Microbiome: Rethinking Health and Disease
journal, October 2012


Mucopurulent Cervicitis — The Ignored Counterpart in Women of Urethritis in Men
journal, July 1984

  • Brunham, Robert C.; Paavonen, Jorma; Stevens, Claire E.
  • New England Journal of Medicine, Vol. 311, Issue 1
  • DOI: 10.1056/NEJM198407053110101

Identification of sRNAs expressed by the human pathogen Neisseria gonorrhoeae under disparate growth conditions
journal, August 2014


Extracts of Canadian First Nations Medicinal Plants, Used as Natural Products, Inhibit Neisseria gonorrhoeae Isolates With Different Antibiotic Resistance Profiles
journal, January 2011

  • Cybulska, Paulina; Thakur, Sidharath D.; Foster, Brian C.
  • Sexually Transmitted Diseases, Vol. 38, Issue 7
  • DOI: 10.1097/OLQ.0b013e31820cb166

Desialylation of Neisseria gonorrhoeae Lipooligosaccharide by Cervicovaginal Microbiome Sialidases: The Potential for Enhancing Infectivity in Men
journal, July 2016

  • Ketterer, Margaret R.; Rice, Peter A.; Gulati, Sunita
  • Journal of Infectious Diseases, Vol. 214, Issue 11
  • DOI: 10.1093/infdis/jiw329

Understanding the Bacterial Flora of the Female Genital Tract
journal, February 2001

  • Larsen, B.; Monif, G. R. G.
  • Clinical Infectious Diseases, Vol. 32, Issue 4
  • DOI: 10.1086/318710

Genomic analyses of Neisseria gonorrhoeae reveal an association of the gonococcal genetic island with antimicrobial resistance
journal, December 2016

  • Harrison, Odile B.; Clemence, Marianne; Dillard, Joseph P.
  • Journal of Infection, Vol. 73, Issue 6
  • DOI: 10.1016/j.jinf.2016.08.010

Gonococcal Infections
journal, February 1985


Vaccine research for gonococcal infections: where are we?
journal, November 2013


Neisseria gonorrhoeae Strain with Reduced Susceptibilities to Extended-Spectrum Cephalosporins
journal, July 2014

  • Nguyen, Duylinh; Gose, Severin; Castro, Lina
  • Emerging Infectious Diseases, Vol. 20, Issue 7
  • DOI: 10.3201/eid2007.131396

FarR Regulates the farAB-Encoded Efflux Pump of Neisseria gonorrhoeae via an MtrR Regulatory Mechanism
journal, December 2003


Effects Of H2 O2-Producing Lactobacilli On Neisseria gonorrhoeae Growth and Activity
journal, November 1994

  • Zheng, H. -Y.; Alcorn, T. M.; Cohen, M. S.
  • Journal of Infectious Diseases, Vol. 170, Issue 5
  • DOI: 10.1093/infdis/170.5.1209

Adaptation of Pseudomonas aeruginosa to various conditions includes tRNA-dependent formation of alanyl-phosphatidylglycerol
journal, February 2009


Emerging azithromycin-resistance among the Neisseria gonorrhoeae strains isolated in Hungary
journal, September 2016

  • Brunner, Alexandra; Nemes-Nikodem, Eva; Jeney, Csaba
  • Annals of Clinical Microbiology and Antimicrobials, Vol. 15, Issue 1
  • DOI: 10.1186/s12941-016-0166-9

Neisseria gonorrhoeae and extended-spectrum cephalosporins in California: surveillance and molecular detection of mosaic penA
journal, December 2013

  • Gose, Severin; Nguyen, Duylinh; Lowenberg, Daniella
  • BMC Infectious Diseases, Vol. 13, Issue 1
  • DOI: 10.1186/1471-2334-13-570

High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure
journal, December 2011

  • Unemo, Magnus; Golparian, Daniel; Nicholas, Robert
  • Antimicrobial Agents and Chemotherapy, Vol. 56, Issue 3
  • DOI: 10.1128/AAC.05760-11

Characterization of the Amino Acids from Neisseria meningitidis MsrA Involved in the Chemical Catalysis of the Methionine Sulfoxide Reduction Step
journal, October 2006

  • Antoine, Mathias; Gand, Adeline; Boschi-Muller, Sandrine
  • Journal of Biological Chemistry, Vol. 281, Issue 51
  • DOI: 10.1074/jbc.M608844200

Fur-Mediated Activation of Gene Transcription in the Human Pathogen Neisseria gonorrhoeae
journal, January 2012


The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae
journal, May 2016

  • Kandler, Justin L.; Holley, Concerta L.; Reimche, Jennifer L.
  • Antimicrobial Agents and Chemotherapy, Vol. 60, Issue 8
  • DOI: 10.1128/AAC.00823-16

Induction of the mtrCDE-encoded efflux pump system of Neisseria gonorrhoeae requires MtrA, an AraC-like protein
journal, August 1999


Changes in the six most common sequence types of Neisseria gonorrhoeae, including ST4378, identified by surveillance of antimicrobial resistance in northern Taiwan from 2006 to 2013
journal, October 2016

  • Cheng, Ching-Wai; Li, Lan-Hui; Su, Chen-Yi
  • Journal of Microbiology, Immunology and Infection, Vol. 49, Issue 5
  • DOI: 10.1016/j.jmii.2014.08.016

Characterization of the OxyR regulon of Neisseria gonorrhoeae
journal, January 2007


Transcript analysis of nrrF, a Fur repressed sRNA of Neisseria gonorrhoeae
journal, March 2009


Novel penA mutations identified in Neisseria gonorrhoeae with decreased susceptibility to ceftriaxone isolated between 2000 and 2014 in Japan
journal, May 2016

  • Seike, Kensaku; Yasuda, Mitsuru; Hatazaki, Kyoko
  • Journal of Antimicrobial Chemotherapy, Vol. 71, Issue 9
  • DOI: 10.1093/jac/dkw161

Clinical Spectrum of Gonococcal Infection in Women
journal, June 1977


Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family
journal, February 1998

  • Shafer, W. M.; Qu, X. - D.; Waring, A. J.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 4
  • DOI: 10.1073/pnas.95.4.1829

CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database
journal, October 2016

  • Jia, Baofeng; Raphenya, Amogelang R.; Alcock, Brian
  • Nucleic Acids Research, Vol. 45, Issue D1
  • DOI: 10.1093/nar/gkw1004

Expression of the Gonococcal Global Regulatory Protein Fur and Genes Encompassing the Fur and Iron Regulon during In Vitro and In Vivo Infection in Women
journal, February 2008

  • Agarwal, S.; Sebastian, S.; Szmigielski, B.
  • Journal of Bacteriology, Vol. 190, Issue 9
  • DOI: 10.1128/JB.01830-07

Experimental Gonococcal Infection in Male Volunteers: Cumulative Experience with Neisseria gonorrhoeae Strains FA1090 and MS11mkC
journal, January 2011

  • Hobbs, Marcia M.; Sparling, P. Frederick; Cohen, Myron S.
  • Frontiers in Microbiology, Vol. 2
  • DOI: 10.3389/fmicb.2011.00123