Role of interferon-gamma inducible chemokines and tissue region in homing of effector leukoctyes to the genital mucosa during Chlamydia trachomatis infection.

摘要

Genital tract (GT) infection with Chlamydia trachomatis generates a cellular immune response that limits Chlamydia infection through production of IFN-gamma and contributes to oviduct damage. The mechanisms responsible for recruitment of inflammatory cells to the GT during Chlamydia infection are not fully defined, nor are the contributions of GT region, which differ anatomically and immunologically. This dissertation addresses these questions and focuses on region-specific induction of IFN-gamma inducible chemokines and recruitment of cells bearing their cognate receptor CXCR3.; Initial studies characterize the chemokine profile of the cervix-vagina (CV) and oviducts (OD) in normal and Chlamydia-infected mice and identify chemokines to investigate functionally in anti-chlamydial leukocyte homing. Results show that basal levels of chemokines are higher in OD than CV; Chlamydia infection further induces pro-inflammatory chemokines and to significantly higher levels in OD compared to CV. These results together with earlier data showing high inflammatory infiltrates in OD but not CV were early demonstrations of differences in the immune response of GT regions during infection and necessitated an evaluation of the effect of inoculate dose on anti-chlamydial immunity. Chemokine induction, cell infiltrates, and OD damage were assessed in mice infected with one of three Chlamydia doses. Results show that dose does not determine the quality of anti-chlamydial immunity, including regional differences in Chemokine patterns. Further, dose significantly influences the magnitude of innate immunity in the GT and innate cells are important in the prevention of chlamydial ascension and OD damage. Final studies identify how regional differences in IFN-gamma inducible Chemokine expression influence effector cell homing to each tissue. The results show that CXCR3 ligands in CV and OD function in recruitment of innate and adaptive cells that contribute to Chlamydia eradication and OD damage.; Taken together, these data support a model of GT immunity during infection that accounts for regional differences in immune effector responses that contribute both to pathogen elimination and tissue damage. These findings are important in the context of Chlamydia vaccine development where chemokines and chemokine receptors are proposed to present novel strategies for regulating the immune response produced against Chlamydia infection.