Reiter's syndrome mechanism of chlamydial pathogenesis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Genital infection with the bacterial pathogen Chlamydia trachomatis is associated with development of reactive arthritis (ReA). While it is clear that the process leading to joint disease is partly immunopathogenic in nature, the means by which C trachomatis initiates and maintains that process remain to be elucidated. Data from this group and others have shown that synovial Chlamydiae display unusual metabolic and transcriptional characteristics and are arrested at a late stage of the developmental cycle. Chlamydiae displaying these and other unusual biologic attributes in vivo are designated to be in the persistent state. Accumulating data further indicate that persistent C. trachomatis cells interact in an overt but poorly understood manner with their host cells. The key to development of effective therapies to treat Chlamydia-associated ReA lies in understanding the biology of chlamydial persistence, and the means by which host and pathogen interact during establishment of that state. In the studies proposed here, we define the genes and gene sets from C. trachomatis that are involved directly or indirectly in establishment and maintenance of the persistent state, using a well-characterized in vitro model of chlamydial persistence. We also, and coordinately, define the changes in expression for specific, targeted sets of host genes as a function of establishment of persistent chlamydial infection in the in vitro model of persistence. The gene sets to be targeted in these analyses will include those from the immune system, the signal transduction system, the energy transduction system, and others. Together, these studies will provide critical new insight not only into chlamydial proteins required for persistence, but also into previously unaddressed interactions between C. trachomatis and its primary host cells. Using information gained from these studies, we will determine the molecular genetic basis for differences between patients who progress to chronic disease and those who do not following genital chlamydial infection, and we define the molecular basis for the remittingrelapsing phenotype of patients with chronic Chlamydia-induced arthritis, and. These latter studies will give important information relating to host-pathogen interaction during various stages of disease progression. Taken together, the results of the studies proposed here will provide a comprehensive understanding of chlamydial persistence and host-pathogen interaction in ReA and therefore will form the foundation for design and implementation of rational strategies to treat the disease.