Chlamydia trachomatis, the most common bacterial sexually transmitted disease (STD) agent worldwide, often establishes asymptomatic genital infections which result in serious reproductive complications. In culture, environmental stressors can induce chlamydiae to enter a viable but non-infectious state termed """"""""persistence"""""""". Persistent chlamydiae: i) can re-enter the normal developmental cycle when the environmental stressor is removed and ii) are refractory to killing by anti-chlamydial drugs. Persistent organisms may also contribute to the long-term inflammation and scarring characteristic of chlamydial diseases by chronically releasing pro-inflammatory effectors and/or by serving as a reservoir for continued cycles of productive infection. Though there is indirect evidence that the persistent state occurs in vivo, direct proof for any role of persistent organisms in chlamydial pathogenesis has remained elusive. The goal of this proposal is to develop an experimentally tractable animal model of persistent chlamydial infection so that the role of persistent organisms in chlamydial pathogenesis can be assessed. Unfortunately, most of the currently characterized persistence inducers (nutrient starvation, IFN-3-exposure, etc.) would be impossible to reproducibly employ in an animal model system. Recent studies in our laboratory indicate that exposure to amoxicillin, the most commonly prescribed 2-lactam in the US, as well as clavulonate, induces C. trachomatis persistence in culture. Additional investigations using C. muridarum-infected mice and C. psittaci- infected cats suggest that amoxicillin/clavulonate (Amox/Clav)-exposed animals develop persistent infection. Amox/Clav is an ideal persistence inducer for use in an animal model as it: i) is relatively non-toxic, ii) acts directly on the developing chlamydiae and iii) can be easily added to or subtracted from the system. Therefore, we will establish an in vivo murine model of C. muridarum persistence by testing the following two hypotheses in two, related, but independent, Specific Aims. Hypothesis 1: Amox/Clav-exposed, persistent chlamydiae can induce alterations in murine host cell gene expression (Aim1). Hypothesis 2: Amox/Clav-exposure can induce persistent chlamydial infection in an in vivo murine model system (Aim 2). Completion of these Aims will not only test both hypotheses but will also provide a necessary foundation for future studies regarding the role of persistent chlamydiae in chronic disease induction. Chlamydia trachomatis is the most commonly reported bacterial STD agent in the US (4,000,000 new cases/year) and worldwide (90 million new cases/year). In women, C. trachomatis genital infection often results in salpingitis, sterility or atopic pregnancy. Genital chlamydial infections cost an estimated $10 billion in the US in 2002. This proposal will develop an experimentally tractable animal model of chlamydial persistence, which will ultimately allow us to determine how persistent infection impacts pathogenesis, transmission and antimicrobial therapy for these infections.
Chlamydia trachomatis is the most commonly reported bacterial STD agent in the US, with 4,000,000 new cases per year. In women, C. trachomatis infection is a common cause of sterility and potentially fatal atopic pregnancy - diseases which cost an estimated $10 billion in the US in 2002. Alarmingly, despite the development of excellent screening tests and effective anti-chlamydial drugs, the incidence of chlamydial genital infections in the US continues to rise. This study will determine whether or not chlamydiae can establish persistent infections in the genital tract, which has important implications for development of better stratigies to prevent disease and new infections.
| Kintner, Jennifer; Lajoie, Dawn; Hall, Jennifer et al. (2014) Commonly prescribed ?-lactam antibiotics induce C. trachomatis persistence/stress in culture at physiologically relevant concentrations. Front Cell Infect Microbiol 4:44 |
| Phillips-Campbell, R; Kintner, J; Schoborg, R V (2014) Induction of the Chlamydia muridarum stress/persistence response increases azithromycin treatment failure in a murine model of infection. Antimicrob Agents Chemother 58:1782-4 |
| Phillips Campbell, R; Kintner, J; Whittimore, J et al. (2012) Chlamydia muridarum enters a viable but non-infectious state in amoxicillin-treated BALB/c mice. Microbes Infect 14:1177-85 |
| Schoborg, R V (2011) Chlamydia persistence -- a tool to dissect chlamydia--host interactions. Microbes Infect 13:649-62 |
