Microbial pathogens which invade the genital mucosa have specific mechanisms which involve adherence, invasion, intracellular survival and exit as a means of production of pathogenicity. C. trachomatis is the most common sexually transmitted bacterial pathogen in this country causing about 4.5 million cases of chlamydia in men, women, and children. The majority of chlamydial infections in women are asymptomatic, sequealae of untreated infections are an important part of the pathogenesis of the disease. Infections due to N. gonorrhoeae, like those of C. trachomatis, remain a major cause of STDs. Further, they remain a major cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy and chronic pelvic pain in the United States. Epidemiologic data provide strong evidence that gonococcal infections facilitate the transmission of other STDs and studies have begun to elucidate the specific mechanisms through which this facilitation occurs(). In 1996, there were greater than 325,000 cases of gonorrhea reported in the United States. However, this rate has continued to decline since 1975 but still remains a significant cause of disease. Although adequate antimicrobial therapy exists for this infection rates are high (17 percent/100,000 population) and antimicrobial resistance is significant (29 percent of all isolates collected in 1996 were resistant to penicillin, tetracycline or both). Therefore, alternate methods of controlling the infection remains a high priority. Toward this end, we are aggressively pursuing antimicrobials which have potential as topical microbicides. Therefore, there is a critical need to find a microbicide that would interact with these pathogens either prior to or at the point of interaction with cells of the genital mucosa. We have decided to study a variety of chemical agents including detergents, bile salts and other compounds to determine their antichlamydial and antigonococcal activity in both in vitro assays using cell cultures and the human fallopian tube organ culture model. This proposal will address several questions which are central to the determination of useful microbicidal agents which will interrupt the interaction between the chlamydial elementary body and/or gonococci and receptors on the host cell surface.
The specific aims of this proposal are: (1) To expand the human primary cell culture systems to evaluate in vitro the efficacy and cytotoxicity of potential topical antimicrobials to prevent infection of the genital mucosa by Chlamydia trachomatis and/or Neisseria gonorrhoeae. (2) Define the mechanism(s) by which select non-cytotoxic candidate topical antimicrobials inhibit C. trachomatis and/or N. gonorrhoeae and (3) Isolate the HS glycosaminoglycans (GAGs) from human genital tract cells and organ cultures and identify fractions important for C. trachomatis adherence to cells. These studies should allow a detailed study of antimicrobials which will allow their potential as topical microbicides to be exploited.
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