Host Factors in Susceptibility to Chlamydial Disease

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DESCRIPTION (provided by the applicant): Chlamydia trachomatis infections are the most commonly reported transmissible diseases in the U.S. Diagnosis, treatment, and sequelae of chlamydial disease cost billions of dollars each year in the U.S. alone. The infection is often asymptomatic in women. Variations in the host immune response are likely to blame for adverse outcomes because not all persons who become infected will suffer the long-term consequences of the disease. In those who progress to disease, the affected tissues are significantly altered in their structure and function by a process that ultimately results in scarring and blockage of the fallopian tubes. This results in tubal factor infertility and risk of ectopic pregnancy. Our hypothesis is that those who sustain this outcome have dysregulation of factors which are responsible for the repair of the extracellular matrix. To address hypothesis, we will use a mouse model of chlamydial disease where inbred strains exist which have been characterized as resistant or susceptible as indicated by the outcomes of tubal damage and infertility. In approach, we will first extensively compare and contrast these strains with regard to their ability to modify and repair the extracellular matrix of the urogenital tract in vivo and in vitro. Subsequently, we will define the role of matrix metalloproteinases (MMPs) in the outcome of chlamydial disease through in vivo studies where the enzymes are inhibited pharmacologically or cytokines that influence their activity and production are neutralized. We will then define a role of specific metalloproteinases to the disease process through the use of mice with deletions in genes that encode the enzymes. Lastly, the contribution of specific inflammatory cells to the modulation of extracellular matrix in chlamydial disease will be defined by the production of bone marrow chimeras between susceptible and resistant strains of mice and subsequent depletions of leukocyte populations. In summary, it is the intent of this proposal to define host factors that are responsible for adverse chlamydial disease outcome. The information derived will assist in the development of therapies which could ameliorate the chlamydial disease process; noninvasive diagnostic indicators of progressive scarring and abnormal physiological outcome; development of prognostic indicators of those at high risk for chlamydial disease; and, further advances in design of a safe and effective chlamydial vaccine through avoidance of adverse outcomes.