Diagnosis and treatment of Sexually Transmitted Diseases (STDs) cost <15.9 billion dollars in the US in 2000. Genital Chlamydia trachomatis (2,800,000 new cases/year) and Herpes Simplex Virus type 2 (HSV-2;200- 500,000 new cases/year + <40 million currently infected) infections can cause a variety of serious complications. Our long-term goals are to: i) determine if co-infection with multiple STD agents alters pathogenesis or transmission;and ii) identify host determinants that influence STD pathogenesis. C. trachomatis, an obligate intracellular bacterium, can enter a viable but non-infectious state called persistence. Our data demonstrate that either HSV-2 co-infection or contact between purified HSV-2 virion glycoprotein D (gD) and the host genital epithelial cell adhesion protein, nectin-1 (nec-1), induces C. trachomatis serovar E persistence. C. trachomatis co-infection also increases host cell HSV-2 production. These data demonstrate that co-infection can alter STD agent replication and suggest that HSV gD/host nec-1 interaction activates a novel epithelial cell pathway that regulates chlamydial development. Notably, i) endogenous host nec-1 ligands are differentially expressed in the human genital tract;ii) persistent chlamydiae may increase inflammation in vivo;and iii) persistent organisms are resistant to killing with antibiotics. These data suggest that nec-1 stimulation (via HSV gD or endogenous nec-1 ligands) may induce persistence, subsequently increasing disease severity or reducing antibiotic effectiveness in vivo. Augmented virus shedding, induced by either co-infection or contact with chlamydial antigens, could also increase HSV transmission. Thus, we will test the following two hypotheses in four focused, but independent, Specific Aims: Hypothesis 1: Interaction of host nec-1 with HSV gD and/or endogenous host nec-1 ligands activates a host cellular response that restricts chlamydial development in genital epithelial cells. Hypothesis 2: Chlamydial pre-infection of the host cell enhances HSV production by increasing viral gene expression.
In Aim 1, chlamydiae-infected cells will be exposed to the 3 known endogenous host nec-1 ligands to determine whether they induce chlamydial persistence.
In Aim 2, specific inhibitors of host signaling will be used to determine which pathways are required for persistence induction.
In Aim 3, HSV binding/entry and mRNA/DNA accumulation in C. trachomatis pre-infected cells will be measured. Finally, in Aim 4, pathogen shedding will be examined in vaginally co-infected wildtype mice as well as in chlamydiae-singly infected, nec-1 -/- mice. These experiments will: i) identify specific candidates for host ligand(s) and signal transduction cascade(s) involved in nec-1-induced chlamydial persistence;ii) determine whether chlamydial persistence and enhanced HSV production observed within co-infected cell cultures occur in vivo;iii) explore nec-1's role in host restriction of chlamydial development;and iv) provide a necessary foundation for future in vitro and in vivo studies of chlamydiae/host cell interaction and pathogenesis of polymicrobial STDs.

Public Health Relevance

The bacterium Chlamydia trachomatis (4,000,000 new cases/year) and the virus Herpes Simplex Virus type 2 (200,000-500,000 new cases/year) are common causes of Sexually Transmitted Disease in the US. Herpes Simplex Virus binding to a human genital cell activates a novel response that inhibits C. trachomatis development within that host cell. This study will explore this inhibitory host response, which may lead, in the future, to development of new drugs that control chlamydial infection by activating this response.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Hiltke, Thomas J
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East Tennessee State University
Schools of Medicine
Johnson City
United States
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Borel, Nicole; Leonard, Cory; Slade, Jessica et al. (2016) Chlamydial Antibiotic Resistance and Treatment Failure in Veterinary and Human Medicine. Curr Clin Microbiol Rep 3:10-18
Slade, Jessica A; Hall, Jennifer V; Kintner, Jennifer et al. (2016) Host Nectin-1 Promotes Chlamydial Infection in the Female Mouse Genital Tract, but Is Not Required for Infection in a Novel Male Murine Rectal Infection Model. PLoS One 11:e0160511
Slade, Jessica; Hall, Jennifer V; Kintner, Jennifer et al. (2016) Chlamydial Pre-Infection Protects from Subsequent Herpes Simplex Virus-2 Challenge in a Murine Vaginal Super-Infection Model. PLoS One 11:e0146186
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