Neisseria Neisseria gonorrhoeaegonorrhoeae

Nealia HouseNealia House

GonorrheaGonorrhea

Topic OverviewTopic Overview Biology of Biology of Neisseria gonorrhoeaeNeisseria gonorrhoeae

– Survival Within HostSurvival Within Host ScreeningScreening TreatmentTreatment Control/SurveillanceControl/Surveillance

http://www2.chemie.uni-erlangen.de/education/medchem/harnsteine/urs_infektion.html

GonorrheaGonorrhea

Sexually transmitted diseaseSexually transmitted disease Infection RateInfection Rate

– socioeconomic classsocioeconomic class– AgeAge

Very common infectious diseaseVery common infectious disease– STI second only to chlamydiaSTI second only to chlamydia

Increasing antibacterial resistanceIncreasing antibacterial resistance Increases efficiency of HIV transmissionIncreases efficiency of HIV transmission

http://www.cat.cc.md.us/courses/bio141/labmanua/lab1/dkngon.html

Affected PopulationsAffected Populations

http://www.agi-usa.org/pubs/ib_std.html

STI Rates World-Wide

GonorrheaGonorrhea Humans only natural Humans only natural

hosthost– Reproductive tractReproductive tract

Infection can be Infection can be asymptomaticasymptomatic– InfertilityInfertility

Several tests Several tests available for available for detection of detection of gonorrheagonorrhea

http://evolution.berkeley.edu/evosite/relevance/images/Kunkel_97210C.jpg

GonorrheaGonorrhea

Topic OverviewTopic Overview Biology of Biology of Neisseria gonorrhoeaeNeisseria gonorrhoeae

– Survival Within HostSurvival Within Host ScreeningScreening TreatmentTreatment Control/SurveillanceControl/Surveillance

http://www.nature.com/genomics/images/neisseria_200.jpg

TransmissionTransmission

Does not survive in the environment, Does not survive in the environment, must be transmitted through contactmust be transmitted through contact– Unprotected sexUnprotected sex– Contact with eyes, mouthContact with eyes, mouth– Mother to child during birthMother to child during birth

Neonatal hyperacute purulent conjunctivitis

http://www.aafp.org/afp/980215ap/morrow.html

TransmissionTransmission

Transmissibility dependent on:Transmissibility dependent on:– StrainStrain– Male to female transmission more effectiveMale to female transmission more effective

Higher number of organisms present in male Higher number of organisms present in male urethral discharge than female vaginal secretionsurethral discharge than female vaginal secretions

http://www.biology.arizona.edu/human_bio/problem_sets/stds/graphics/Gonorrhea.gif

StructureStructure

DiplococcusDiplococcus Gram-negativeGram-negative Fimbriae extend several micrometers Fimbriae extend several micrometers

from cell surfacefrom cell surface

http://textbookofbacteriology.net/BSRP.html

http://gsbs.utmb.edu/microbook/images/fig97_2.JPG

http://www.infocompu.com/adolfo_arthur/ingles/gonorrea.htm

http://www.dermnet.com/thumbnailIndex.cfm?moduleID=16&moduleGroupID=234&groupIndex=0&numcols=0

Systemic InfectionSystemic Infection

InfectionInfection

N. gonorrhoeae N. gonorrhoeae attaches to mucosal cells attaches to mucosal cells via pili and other surface proteinsvia pili and other surface proteins

Induces production of inflammatory Induces production of inflammatory cytokines by epithelial cellscytokines by epithelial cells

http://www.brown.edu/Courses/Bio_160/Projects1999/av/gonorrhea.html

InfectionInfection

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.figgrp.898

Survival Within HostSurvival Within Host Evades host immune system by Evades host immune system by

changing surface proteinschanging surface proteins– Often asymptomatic infectionOften asymptomatic infection

The RdgC protein is required for The RdgC protein is required for efficient pilin antigenic variation efficient pilin antigenic variation

http://www.brown.edu/Courses/Bio_160/Projects1999/av/gonorrhea.html

Antigenic VariationAntigenic Variation

Pilus promotes attachment of Pilus promotes attachment of gonococcal cell to host epithelial cellgonococcal cell to host epithelial cell– Must retain some consistencyMust retain some consistency

Conserved N-terminal and variable C-Conserved N-terminal and variable C-terminal regionsterminal regions– Constant regionsConstant regions– Semi-variable regionsSemi-variable regions– Hypervariable regionsHypervariable regions

Phase variation from piliated to non-Phase variation from piliated to non-piliatedpiliated

Immune MemoryImmune Memory

Infection history did not alter antibody Infection history did not alter antibody levels in patients with current infectionlevels in patients with current infection– Suggests immunological memory not Suggests immunological memory not

induced by uncomplicated gonococcal induced by uncomplicated gonococcal infectionsinfections

Local and systemic immune responses Local and systemic immune responses to gonococci extremely modestto gonococci extremely modest– Slight increase in serum immunoglobulin Slight increase in serum immunoglobulin

G (IgG) in infected malesG (IgG) in infected males– Slight increase in serum IgA1 antibodies Slight increase in serum IgA1 antibodies

in infected femalesin infected females

Survival Within HostSurvival Within Host

Pili, outer membrane Pili, outer membrane proteins, lipopolysaccharidesproteins, lipopolysaccharides– Binding to epithelial surfacesBinding to epithelial surfaces– Passage through epitheliumPassage through epithelium– Interaction with phagocytesInteraction with phagocytes

Variations in outer Variations in outer membrane protein (P1, Por)membrane protein (P1, Por)

RequiresRequires– Carbon dioxideCarbon dioxide– Sulfur in form of cysteineSulfur in form of cysteine– IronIron

http://www.med.monash.edu.au/assets/images/microbiology/gono.jpg

Antimicrobial ResistanceAntimicrobial Resistance

Gonococcal strains resistant to:Gonococcal strains resistant to:– PenicillinsPenicillins– TetracyclinesTetracyclines– SpectinomycinSpectinomycin– FluoroquinolonesFluoroquinolones

Presently, ciprofloxacin and ofloxacin Presently, ciprofloxacin and ofloxacin recommended by CDC for treatmentrecommended by CDC for treatment

BiotechnologyBiotechnology

Oligonucleotide chips now used to Oligonucleotide chips now used to screen for antimicrobial resistancescreen for antimicrobial resistance– Point mutations in the gyrA and parC Point mutations in the gyrA and parC

genesgenes Determine the prevalence of ciprofloxacin-

resistant strains

Results identical to sequencing results

Rapid and reliable analysis

GonorrheaGonorrhea

Topic OverviewTopic Overview Biology of Biology of Neisseria gonorrhoeaeNeisseria gonorrhoeae

– Survival Within HostSurvival Within Host ScreeningScreening TreatmentTreatment Control/SurveillanceControl/Surveillance

http://thailabonline.com/bacteria7.htm

ScreeningScreening

““Gold Standard”Gold Standard”– Nucleic acid amplification assaysNucleic acid amplification assays

Polymerase chain reactionPolymerase chain reaction Cell culture to confirm diagnosisCell culture to confirm diagnosis

– Oxidase positiveOxidase positive

http://education.med.nyu.edu/courses/microbiology/courseware/infect-disease/Gram_Neg_Bacilli5.html

Types of TestsTypes of Tests

Gram-Stained SmearGram-Stained Smear– Sensitivity reduced in asymptomatic Sensitivity reduced in asymptomatic

infectionsinfections– Less that 50% sensitive as cell cultureLess that 50% sensitive as cell culture– Not useful in rectal infections Not useful in rectal infections

http://www.lahey.org/Medical/InfectiousDiseases/ID_Gonorrhea.asp

Types of TestsTypes of Tests

Culture Based SystemsCulture Based Systems– High degree of specificityHigh degree of specificity– ExpensiveExpensive– Trained personnelTrained personnel– Media requirementsMedia requirements– Presumptive identificationPresumptive identification

Growth on selective GC agar, gram stain, Growth on selective GC agar, gram stain, oxidase and superoxol positivityoxidase and superoxol positivity

http://www.asu.edu/it/spotlight/archive/genesis/

Types of TestsTypes of Tests

Antigen Detection and Antigen Detection and Enzyme ImmunoassaysEnzyme Immunoassays– Extensively investigatedExtensively investigated

Low/high prevalenceLow/high prevalence Symptomatic/asymptomaticSymptomatic/asymptomatic

– Few to no situations for Few to no situations for which this assay which this assay recommendedrecommended Because of antigenic Because of antigenic

variationvariation

http://wfrc.usgs.gov/research/fish%20populations/STMaule5.htm

Types of TestsTypes of Tests

DNA Probe HybridizationDNA Probe Hybridization– Specific chemiluminescent label on Specific chemiluminescent label on

probeprobe– Available commerciallyAvailable commercially– 85% sensitivity85% sensitivity– 99% specificity99% specificity

http://www.ebiotrade.com

Types of TestsTypes of Tests

Nucleic Acid-Based Amplification Assays Nucleic Acid-Based Amplification Assays (NAAT)(NAAT)– 95% accurate95% accurate– False positives due to specimen cross-False positives due to specimen cross-

contamination, environmental contaminationcontamination, environmental contamination

http://www.biologicalprocedures.com/bpo/arts/1/6/m6.htm

Current ScreeningCurrent Screening

No test for samples from all major No test for samples from all major sites of gonococcal infectionsites of gonococcal infection– RapidRapid– InexpensiveInexpensive– ReliableReliable

Such a test would improve case-Such a test would improve case-findingfinding– Efficient treatmentEfficient treatment– Disease managementDisease management

GonorrheaGonorrhea

Topic OverviewTopic Overview Biology of Biology of Neisseria gonorrhoeaeNeisseria gonorrhoeae

– Survival Within HostSurvival Within Host ScreeningScreening TreatmentTreatment Control/SurveillanceControl/Surveillance

http://neisseria.org/ng/images/

TreatmentTreatment

http://www.cdc.gov/STD/treatment/4-2002TG.htm#Gonococcal

TreatmentTreatment FluoroquinolonesFluoroquinolones

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.figgrp.686

http://www.m-ww.de/pharmakologie/arzneimittel/antiinfektiva/antibiotika/ofloxacin.html

Ofloxacin

Ciprofloxacin

Levofloxacin

http://www.alchemchina.com/products/apis_l.files/Levofloxacin.gif

TreatmentTreatment Ceftriaxone (RocephinCeftriaxone (Rocephin®®))

– Single dose intramuscularly Single dose intramuscularly – Introduced as treatment in 1985Introduced as treatment in 1985

Retained resistanceRetained resistance

– Beta-lactam antibioticBeta-lactam antibiotic– Action against penicillinaseAction against penicillinase

http://www.m-ww.de/pharmakologie/arzneimittel/antiinfektiva/antibiotika/ceftriaxon.html

TreatmentTreatment

Possible co-infection with Possible co-infection with Chlamydia Chlamydia trachomatistrachomatisAzithromycin

Doxycycline

http://www.bmb.leeds.ac.uk/mbiology/ug/ugteach/icu8/images/antibiotics/azithromycin.gif

http://www.cbwinfo.com/Pharmaceuticals/Structures/Doxycycline.gif

VaccineVaccine Hard to developHard to develop

– No animal modelNo animal model No immune memory to No immune memory to Neisseria Neisseria

gonorrhoeaegonorrhoeae– Antigenic variation strategyAntigenic variation strategy

Difficulty finding target common to all Difficulty finding target common to all strainsstrains

Research continues to identify possible Research continues to identify possible vaccine targetsvaccine targets– DNA vaccinesDNA vaccines– Mucosal immunizationMucosal immunization

GonorrheaGonorrhea

Topic OverviewTopic Overview Biology of Biology of Neisseria gonorrhoeaeNeisseria gonorrhoeae

– Survival Within HostSurvival Within Host ScreeningScreening TreatmentTreatment Control/SurveillanceControl/Surveillance

http://www.mediscan.co.uk/cfm/img_coll.cfm?action=search&imageID=020864&collectionID=21&name=Electron%20Micrographs&log=nk#

PreventionPrevention

AbstinenceAbstinence Safe/”smart” sexSafe/”smart” sex Barrier contraceptivesBarrier contraceptives Educational programsEducational programs Reduce misuse of Reduce misuse of

antimicrobialsantimicrobialshttp://www.pueblo.gsa.gov/cic_text/health/contracept/condom.gif

Governmental ProgramsGovernmental Programs Health CanadaHealth Canada

– Educational plansEducational plans– STD ScreeningSTD Screening– Free STD clinicsFree STD clinics

Governmental ProgramsGovernmental Programs CDC Gonococcal Isolate Surveillance CDC Gonococcal Isolate Surveillance

Project (GISP)Project (GISP)

ConclusionsConclusions

More researchMore research– Reliable, fast Reliable, fast

screeningscreening– Preventative Preventative

therapeuticstherapeutics Non-biotechnological Non-biotechnological

interventionsinterventions Prudent Prudent

antimicrobial useantimicrobial usehttp://www.agma.med.uni-giessen.de/cfagma/andro/verz.dbm

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