Impact of HSV-2 shedding on the vaginal microbiome in the female genital tract
Impact of HSV-2 shedding on the vaginal microbiome in the female genital tract
批准号:
8879037
负责人:
CHRISTINE MICHELLE JOHNSTON
金额:
$20.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
关键词:
AcyclovirAddressAntiviral AgentsBacteriaBacterial VaginosisBiological AssayCCR5 geneCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCervix UteriClinicalCommunitiesComplexCoupledDataDetectionDevelopmentDiagnosisDiseaseEconomic BurdenEnrollmentEpidemicEpidemiologyFemaleFrequenciesGenital systemGoalsGram&aposs stainHIVHIV InfectionsHigh-Throughput Nucleotide SequencingHuman Herpesvirus 2ImmuneImmune responseImmunologicsInfectionInflammationInflammatoryInflammatory ResponseInterferon Type IIInterventionKnowledgeLactobacillusLeadLesionLinkMaintenanceMeasuresMediatingMethodsMolecularMorbidity - disease rateMucous MembraneNatural HistoryNatureParticipantPhenotypeProcessProteinsRecording of previous eventsRecurrenceReproductive HealthResearchRiskRisk FactorsSamplingSexually Transmitted DiseasesSimplexvirusSiteSkinSpecimenSurfaceSwabT-LymphocyteTimeTissuesUniversitiesVaginaWashingtonWomanantileukoproteasebasecytokineexperiencegenital herpesgenital secretionhuman SLPI proteinimprovedinflammatory markerinnovationinsightinterestmicrobialmicrobiomemortalitynovelpathogenpyrosequencingrRNA Genesresponseroutine Bacterial stainsample collectionseropositivetherapy designvaginal fluid
中文摘要
项目总结
英文摘要
Project Summary
Herpes simplex virus type 2 (HSV-2) and bacterial vaginosis (BV) are two of the most prevalent infections of
the female genital tract. Both infections are associated increased risk for HIV acquisition. While HSV-2 and
BV have been epidemiologically linked in many studies, the direction and mechanism of their interaction is not
known. Our group has pioneered daily participant-collected sampling to show that HSV-2 is detected ("shed")
frequently, on 10-28% of days, from genital surfaces, and that HSV-2 shedding is asymptomatic the majority of
the time. More recent data has demonstrated that HSV-2 genital lesions and asymptomatic shedding episodes
are associated with a persistent inflammatory cellular response, with IFN-γ producing HSV-specific CD4+ and
tissue resident CD8+ T-cells. These data suggest that HSV-2 infection chronically and fundamentally alters
inflammation the genital tract. Drs. Marrazzo and Fredricks have similarly used frequent vaginal sampling and
molecular methods to document rapid shifts in the vaginal microbiome, and to discover novel BV-associated
bacteria (BVAB). This proposal seeks to elucidate the temporal and mechanistic nature of the HSV-2/BV
association and to identify the components of the inflammatory response to HSV-2 that may increase the risk
of BV. We hypothesize that frequent HSV-2 genital shedding causes increased levels of inflammatory
cytokines, such as IL-1ß and IFN-γ, and decreased levels of antiviral innate immune molecules (i.e. secretory
leukocyte protease inhibitor, SLPI) and that these changes result in fluctuations in the vaginal microbiome
which predispose women to develop BV. To address these hypotheses, we will enroll 40 HSV-2 seropositive,
HIV seronegative women with a history of BV in the past year who will self-collect genital and vaginal
specimens daily for 30 days. We will also enroll 20 HSV-2 seropositive women without a clinical history of BV.
We will quantify HSV using a validated PCR assay, and we will measure changes in the microbiome using
gram stain (Nugent score), quantitative PCR (qPCR) and broad range 16S rRNA gene PCR with high
throughput sequencing during HSV shedding episodes. Daily vaginal levels of innate immune proteins and
cytokines associated with HSV-2 shedding will be measured. Relationships between HSV-2 shedding and
Nugent score, quantity and presence of BVAB, and cytokine levels will be determined. These women will then
be placed on suppressive acyclovir, which decreases HSV-2 shedding by 70-80%. We will determine whether
suppression of HSV-2 shedding results in improved vaginal flora as measured by a decrease in Nugent score
and increased concentration of lactobacilli. This integrated proposal will determine the relationship between
HSV-2 shedding and the vaginal microbiome, and will give insight into the mechanistic basis of the association
to provide a framework for appreciating how these infections influence inflammation within the genital tract.
Ultimately, this proposal will contribute vital and novel information to the design of interventions that can
modulate BV, and will provide us with knowledge to better promote women's reproductive health.
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Interaction between HSV-2 and the vaginal microbiome in the female genital tract
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批准号:8510889
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项目类别:
-
资助金额:$60.37万
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财政年份:2012
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Dynamic Reactivation of Herpes Simplex Virus-2 and the Genital Mucosal Response
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批准号:7513541
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项目类别:
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资助金额:$11.86万
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财政年份:2008
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Dynamic Reactivation of Herpes Simplex Virus-2 and the Genital Mucosal Response
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批准号:7644973
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项目类别:
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资助金额:$12.13万
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财政年份:2008
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Dynamic Reactivation of Herpes Simplex Virus-2 and the Genital Mucosal Response
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批准号:8074906
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项目类别:
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资助金额:$12.7万
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财政年份:2008
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Dynamic Reactivation of Herpes Simplex Virus-2 and the Genital Mucosal Response
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批准号:7810546
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项目类别:
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资助金额:$12.41万
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财政年份:2008
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Genital HSV-1: An Emerging Disease
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批准号:8565778
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项目类别:
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资助金额:$15.06万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Impact of HSV-2 shedding on the vaginal microbiome in the female genital tract
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批准号:9308822
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项目类别:
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资助金额:$23.2万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Genital HSV-1: An Emerging Disease
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批准号:8696992
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项目类别:
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资助金额:$16.7万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Clinical Core
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批准号:9307676
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项目类别:
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资助金额:$32.29万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Genital HSV-1: An Emerging Disease
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批准号:9307675
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项目类别:
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资助金额:$17.94万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Genital HSV-1: An Emerging Disease
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批准号:8890054
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项目类别:
-
资助金额:$15.7万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Impact of HSV-2 shedding on the vaginal microbiome in the female genital tract
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批准号:8769640
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项目类别:
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资助金额:$16.66万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Clinical Core
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批准号:8696993
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项目类别:
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资助金额:$32.08万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
Clinical Core
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批准号:8565779
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项目类别:
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资助金额:$28.73万
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财政年份:--
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负责人:CHRISTINE MICHELLE JOHNSTON
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依托单位:
海外基金