In women, the manifestations of C. trachomatis infection range from asymptomatic cervicitis to pelvic inflammatory disease, infertility, and ectopic pregnancy. Variations in outcomes suggest humans exhibit heterogeneity in host susceptibility to chlamydial disease. A genetic influence on disease susceptibility is supported by epidemiological studies in humans, and in animal models of experimental infection. The candidate has confirmed that true differences exist among three genetically defined strains of mice as regards resolution of chlamydial genital tract infection and the development of pathological sequelae. Despite these differences, extensive data reveal their acquired immune responses to be similar - CD4+ T cells of the Th 1 phenotype are critical to recovery from chlamydial infection. In contrast, comparisons of responses active during the first week of infection reveal significant differences in early cellular and cytokine response mediators. This proposal involves using the inherent differences present in these strains of mice as a tool for examining cytokine regulatory pathways important in chlamydial disease pathogenesis. The significance of the different patterns of cytokine responses determined among the three strains will be further explored with mice genetically deficient in specific cytokine mediators. Specific aims of the proposal include: 1) confirmation of the role of TNF-alpha and of neutrophils in early control of chlamydial infection and determination of their role in the development of chronic pathology; 2) delineation of the contribution of other proinflammatory cytokines (interleukin-1 and interleukin-6) and of select chemokines to host defense and immunopathology; 3) determination if different kinetics of the downregulatory cytokines, TGF-beta and interleukin-10, influence the course and outcome of chlamydial genital tract infection. A determination of cytokine response patterns that promote tissue damage from those that result in benign resolution of infection is an important goal as regards the development of a safe and effective chlamydial vaccine.