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Principal Investigator: CATHERINE MARY O'CONNELL
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2022
Award: $337,380
Funding agency: National Institute of Allergy and Infectious Diseases
In a subset of Chlamydia trachomatis-infected women, the infection escapes immune control and ascends to the
upper reproductive tract. There is a fundamental gap in understanding how pathways activated by chlamydial
infection lead to immune pathology and reproductive morbidity in women. Its continued existence is a significant
barrier to identification of biomarkers to diagnose or predict risk for reproductive sequelae after exposure. The
long-term goal of this program is to develop vaccines that reduce transmission and prevent reproductive tract
sequelae after exposure to C. trachomatis. The overall objective of this proposal is to identify biomarkers of
asymptomatic ascending infection and endometritis in women and genetic biomarkers of susceptibility/risk for
disease. The central hypothesis is that protective and immunopathologic responses elicited in response to STI
associate with characteristic transcriptional signatures and genetic variance. The rationale for this project is that
identifying biomarkers of susceptibility to ascending infection and risk for subsequent immune pathology will
accelerate rational vaccine design and testing by (i) identifying individuals most likely to benefit from
immunization, to facilitate appropriately powered studies, (ii) enabling balanced group selection for vaccine trials,
and (iii) serving as clinical measures of vaccine efficacy. Blood-borne transcriptional profiling of women with a
spectrum of chlamydial genital tract infection revealed specific inflammatory pathways associated with disease
and enabled definition of a biomarker panel that diagnoses endometritis in asymptomatically-infected women
with high chlamydial burden. Guided by strong preliminary data, the following three specific aims will test the
hypothesis: 1) Determine candidate biomarkers positively- or negatively associated with ascending chlamydial
infection in asymptomatic women; 2) Identify genetic biomarkers of susceptibility to ascending chlamydial
infection and risk for subsequent reproductive sequelae; and 3) Identify disease-causing pathways and their key
regulators engaged during ascending chlamydial infection, using causal network analysis. The first aim will profile
cervical inflammatory responses from women with local infection or upper tract involvement in a new cohort of
highly-exposed women (TRAC2, Core B). Pathogen load, co-infection, cervicovaginal microbiome and hormonal
contraceptives will be assessed as confounders or additional biomarkers. The remaining aims will focus on
integrating genotype, gene expression and disease phenotypes from TRAC2 and previously-profiled cohorts via
expression quantitative trait locus (eQTL) mapping and causal mediation test, and on identification of disease-
causal genes, using graphical models. The research proposed is innovative, in our opinion, because it will
implement a comprehensive, non-biased approach to the identification of molecular biomarkers in a highly
disease-relevant clinical population. The proposed research is significant because it is expected to translate
directly to anti-chlamydial vaccine evaluation in humans and to have broad importance for diagnosis and for
evaluation of novel therapeutics.
Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><Acute><Automobile Driving><Biological Markers><Blood><Blood Reticuloendothelial System><C trachomatis><C. trachomatis><Cannot achieve a pregnancy><Cervical><Cervix><Cervix Uteri><Characteristics><Chlamydia><Chlamydia Infections><Chlamydia trachomatis><Chlamydial Infection><Clinical><Contraceptive Usage><DNA><Data><Deoxyribonucleic Acid><Diagnosis><Diagnostic Sensitivity><Difficulty conceiving><Disease><Disease Pathway><Disorder><Ectopic Pregnancy><Endometritis><Evaluation><Exposure to><Expression Signature><Female Health><Focal Infection><Gene Chips><Gene Expression><Gene Expression Chip><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><GeneChip><Genes><Genetic><Genetic Markers><Genotype><Goals><High Risk Woman><Human><Immune><Immune response><Immunes><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Individual><Infection><Infertility><Inflammatory><Inflammatory Response><Knowledge><Lead><Link><Measures><Mediation><Messenger RNA><Miyagawanella><Modeling><Modern Man><Molecular><Monitor><NIH><National Institutes of Health><Negotiating><Negotiation><Network Analysis><North Carolina><Oral Contraceptives><Outcome><Participant><Pathology><Pathway Analysis><Pathway interactions><Pb element><Pelvic Inflammatory Disease><Population><Predisposition><Preventative vaccine><Prevention><Preventive vaccine><Process><Prophylactic vaccine><QTL><Quantitative Trait Loci><Reproductive Health><Research><Research Design><Resolution><Rickettsia trachomae><Risk><SNP array><SNP chip><Source><Study Type><Surrogate End Points><Surrogate Endpoint><Susceptibility><Testing><Transcript Expression Analyses><Transcript Expression Analysis><Translating><Transmission><Treatment Efficacy><United States National Institutes of Health><Universities><Uterine Cervix><Vaccine Design><Vaccines><Woman><Women's Health><Work><adaptive immune response><bedsonia><bio-markers><biologic marker><biomarker><biomarker identification><biomarker panel><birth control pill><candidate biomarker><candidate marker><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cervicovaginal microbiome><chlamydia vaccine><chlamydial disease><chronic pelvic pain><chronic pelvic pain syndrome><clinical relevance><clinically relevant><co-infection><cohort><coinfection><contraceptive use><cost><develop a vaccine><develop vaccines><development of a vaccine><diagnosis evaluation><disease phenotype><disease risk><disorder risk><driving><evaluate vaccines><expression array><extrauterine pregnancy><fertility cessation><fertility loss><gene expression analysis><gene expression assay><gene expression microarray><gene expression pattern><gene expression signature><genetic biomarker><genital tract><genome scale><genome-wide><genomewide><heavy metal Pb><heavy metal lead><hormonal contraception><hormonal contraceptive><host response><immune system response><immunoresponse><improved><infection localized><infection risk><infertile><innovate><innovation><innovative><intervention efficacy><local infection><long-term sequelae><mRNA><marker identification><marker panel><molecular biomarker><molecular marker><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathogen><pathway><pelvic inflammation disease><pelvic inflammation disorder><pelvic inflammatory disorder><pelvic inflammatory syndrome><prevent><preventing><programs><recruit><reproductive><reproductive morbidity><reproductive tract><response><single nucleotide polymorphism array><single nucleotide polymorphism chip><study design><therapeutic efficacy><therapy efficacy><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptomics><transmission process><vaccination study><vaccination trial><vaccine development><vaccine efficacy><vaccine evaluation><vaccine screening><vaccine study><vaccine testing><vaccine trial><vagina microbiota><vaginal flora><vaginal microbial community><vaginal microbiota><vaginal microflora><women at high risk><work group><working group>