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Principal Investigator: Toni Darville
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2019
Award: $808,098
Funding agency: National Institute of Allergy and Infectious Diseases
DESCRIPTION (provided by applicant): Chlamydia trachomatis infection is the leading cause of infertility and ectopic pregnancy in women. Infection is often asymptomatic, leading to lack of detection, increased risk for disease and delay in treatment. Although antibiotic therapy eliminates infection, it does not mitigate or reverse established destructive pathology. Thus, there is a critical need for an effective preventative approach, in the form of a vaccine. Rational
vaccine design requires understanding of the adaptive mechanisms associated with protective immunity and identification of chlamydial antigens that best elicit protective responses. Animal models and human epidemiologic data indicate that repeated exposure will ultimately protect against reinfection. Resolution of infection by attenuated chlamydial mutants protects against genital and ocular disease, providing evidence that an effective chlamydial vaccine can be developed. Mouse model and human data indicate that IFN-γ-producing, Chlamydia-specific CD4 (Th1) cells are the primary mediators of protective immunity. We have identified chlamydial proteins that elicit IFN-γ production predominantly from CD4 T cells and are significantly associated with protection against chlamydial reinfection in a group of highly sexually active women. Transcriptional profiling of women with chlamydial pelvic inflammatory disease reveal dysregulation of genes involved in T cell growth, proliferation, and signaling. These data support our central hypothesis that protection is dependent on the generation of antigen-specific CD4 T cell responses. Our overall objectives are to validate our novel vaccine candidate antigens, profile the T cells recognizing these antigens, and determine local and systemic responses that lead to an effective anti-chlamydial immune response. Our rationale is that identification of T cel effector activities and antigens associated with protection will advance the development of a vaccine. We will test our central hypothesis by completing the following specific aims: 1. Characterize CD4 and CD8 T cells recognizing chlamydial antigens associated with resistance to reinfection. We will test the hypothesis that polyfunctional central and effector memory CD4 but not CD8 Th1 cells are induced in protected women, using multiparameter flow cytometry, multiplex cytokine and mRNA analyses. 2. Define a transcriptional signature that leads to protection from reinfection. We will use endometrial RNAseq, whole blood and cellular microarrays to elucidate the evolution of a protective adaptive immune response to Chlamydia and to identify surrogate markers of vaccine efficacy. Expected outcomes of this work are important information related to vaccine antigens, T cell memory responses, and signaling pathways that correlate with protection against the world's most prevalent sexually transmitted bacterial pathogen and a leading cause of preventable blindness.
Terms: <(TNF)-α><0-11 years old><ATGN><Advanced Development><Animal Model><Animal Models and Related Studies><Antibiotic Therapy><Antibiotic Treatment><Antigens><Attenuated><Bacterial Gene Products><Bacterial Gene Proteins><Bacterial Proteins><Biological Markers><Blindness><Blood><Blood Reticuloendothelial System><Body Tissues><C trachomatis><C. trachomatis><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cachectin><Cannot achieve a pregnancy><Cell Communication and Signaling><Cell Signaling><Cellular Expansion><Cellular Growth><Cervical><Cervix><Cervix Uteri><Characteristics><Child><Child Youth><Children (0-21)><Chlamydia><Chlamydia Infections><Chlamydia trachomatis><Chlamydial Infection><Communities><Data><Depressed mood><Detection><Developed Countries><Developed Nations><Development><Difficulty conceiving><Disease><Disorder><Ectopic Pregnancy><Endometrial><Epidemiological data><Epidemiology data><Evolution><Expression Signature><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Failure><Fallopian Tubes><Female><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gamma interferon><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Transcription><Generations><Genes><Genetic Transcription><Genital><Genital system><Granzyme><High Risk Woman><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune><Immune Interferon><Immune response><Immunes><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Individual><Industrialized Countries><Industrialized Nations><Infection><Infertility><Inflammatory Response><Innate Immunity><Interferon Gamma><Interferon Type II><Interferon-gamma><Intracellular Communication and Signaling><Knowledge><Lead><MHC Receptor><Macrophage-Derived TNF><Major Histocompatibility Complex Receptor><Mammalian Oviducts><Mechanistic Target of Rapamycin><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Memory><Messenger RNA><Mice><Mice Mammals><Microarray Analysis><Microarray-Based Analysis><Miyagawanella><Modern Man><Molecular Fingerprinting><Molecular Profiling><Monocyte-Derived TNF><Murine><Mus><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Outcome><Pathology><Pathway interactions><Patients><Pb element><Pelvic Inflammatory Disease><Population><Production><Proteins><RAFT1><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Receptors, Antigen, T-Cell><Resistance><Resolution><Rickettsia trachomae><Salpinx><Sexual Transmission><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surrogate Markers><T cell response><T memory cell><T-Cell Receptor><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Th-1 Cell><Th1 Cells><Tissues><Trachoma><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Type 1 Helper Cell><Uterine Cervix><Uterine Tubes><Uterus><Vaccine Antigen><Vaccine Design><Vaccines><Visit><Whole Blood><Whole Organism><Woman><Work><adaptive immune response><adaptive immunity><bacterial disease treatment><bacterial infectious disease treatment><bacterial pathogen><base><bedsonia><bio-markers><biologic marker><biological signal transduction><biomarker><cell growth><children><childrens'><chlamydial disease><chronic pelvic pain><chronic pelvic pain syndrome><cytokine><depressed><develop a vaccine><development of a vaccine><developmental><disease risk><disorder risk><effector T cell><epidemiologic data><extrauterine pregnancy><fertility cessation><fertility loss><flow cytophotometry><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><genital tract><heavy metal Pb><heavy metal lead><high risk><high risk behavior><host response><human data><immunogen><immunoresponse><improved><infertile><lFN-Gamma><mRNA><mTOR><mammalian target of rapamycin><memory T lymphocyte><microarray analyses><microarray technology><model of animal><model organism><molecular profile><molecular signature><mouse model><murine model><mutant><new vaccines><next generation vaccines><novel><novel vaccines><oviduct><pathogen><pathogenic bacteria><pathway><pelvic inflammatory syndrome><public health relevance><recruit><reproductive tract><resistant><response><sadness><sexually active><sexually transmitted><surrogate bio-markers><surrogate biomarkers><thymus derived lymphocyte><transcriptional profiling><transcriptional signature><transcriptome sequencing><vaccine candidate><vaccine development><vaccine efficacy><vaccine formulation><vision loss><visual loss><womb><women at high risk><youngster>