Recent estimates indicate that 4 million new cases of genital Chlamydia trachomatis infection occur yearly, and pelvic inflammatory disease (PID) has been estimated to affect 25 percent of women with genital chlamydia. C. trachomatis appears to produce tubal damage through induction of immunopathologic host responses to the infection. Previous experiments showed that antibiotic and antiinflammatory treatment did not change the outcome of chlamydial salpingitis. However, intrinsic host factors, such as cytokine responses and MHC genotype, may predispose to tubal immunopathology. Persistence of chlamydial infection, as detected by culturable organism, by antigen or by chlamydial DNA in the upper genital tract also appeared to be correlated with immunopathology. In the proposed studies the PI will use multiple cervical C. trachomatis inoculations of female macaques to test whether intrinsic host factors (cytokine response and MHC) predict PID vs cervicitis only, whether persistent chlamydia is viable, and whether treatment reduces chlamydial persistence and viability. Specifically, she will test: 1. Whether a Th1-dominated fibrogenic immune response characterizes the immunopatahology of C. trachomatis infection. The PI will contrast cervical and tubal cytokine responses during C. trachomatis infection between monkeys progressing to PID and those with cervicitis only. 2. Whether specific MHC class I and/or class II alleles predict susceptibility or resistance to PID vs. cervicitis. 3. Whether persistence of viable C. trachomatis in tissue induces PID. She will test for chlamydial mRNA or culturable organism, versus antigen and/or DNA in untreated monkeys with PID vs. cervicitis. 4. Whether clinically relevant antichlamydial antibiotics are effective in reducing chlamydial burden, persistence, viability and immunopathology. Chlamydial immunopathology in the macaque model is highly similar to human cervicitis and salpingitis. The use of cervical inoculations in the macaque model mimics the natural route of infection in women, allowing expression of resistance or susceptibility to ascending infection. The proposed studies will provide new information to guide the development of effective interventions that will prevent or reduce the long term sequelae of C. trachomatis in women.
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