Investigation of immunity and latency to chlamydial infection links host immune responses with chlamydial growth modulation. The concept that chlamydial infections progress to chronic disease has been acknowledged for decades in animals, but is supported by only meager data in humans. Cell culture models do provide proof of principle for the chronic infection (latency) hypothesis. The most compelling mechanistic model is referred to as chlamydial persistence and involves induction of non-productive, but reversible, intracellular chlamydial growth elicited by Th1 immune regulated cytokines (e.g. gamma interferon;IFN-g) on chlamydial host cells. This model has been developed in a variety of human cell culture systems and is based on the induction of an enzyme (indoleamine 2,3-dioxygenase, IDO) that decyclizes tryptophan, creating a nutrient deficient intracellular environment to restrict intracellular chlamydial growth. Study of persistence has, however, been hampered in vivo because appropriate animal models are not available. A major reason for this deficit is that although the mouse is a convenient model for C. trachomatis genital tract disease, murine IFN-g-mediated responses are different from responses observed in humans. Murine immune responses to chlamydiae in wild type animals are likely to result in eradicative immunity rather than persistence, although the full repertoire of lethal and static mouse responses are not yet fully elucidated. Therefore, to gain a better appreciation of requirements for development of chronic chlamydial infections in mice the murine antimicrobial activities elicited by IFN-g will be systematically classified in cell culture (e.g. iNOS, arginase, p47, phox, IDO) using several cell types and primary cells from conventional and knock out mice. Cell culture results will be exploited to study mice that are genetically manipulated or chemically treated to elicit responses that provide an environment conducive to development of chronic chlamydial genital tract infection. Results will provide an improved tractable model of chlamydial persistence, furnish a way to understand more completely the pathogenesis of chronic chlamydial infections, and help define requirements for efficacious vaccine design.
Showing the most recent 10 out of 43 publications
