An infectious etiology for Reiter's syndrome (RS) has long been suspected, since this disease has often been observed to follow episodes of urethritis or dysentery. Although many bacterial species can be associated with the disease, Chlamydia trachomatis has emerged as a primary etiologic agent in RS, due largely to its prevalence in the population. Although this organism is the major sexually-transmitted bacterium in the industrialized world, many aspects of the natural history of such infections remain relatively poorly understood; eg, both epidemiological and clinical features of chlamydial infections suggest that the organism can persist in a culture-negative state under some circumstances. Recent work from this laboratory has provided direct molecular biological evidence for persistent/inapparent chlamydial infections in all anatomically relevant sites; ie, we demonstrated that high levels of chlamydial nucleic acids can be demonstrated, via a simple molecular hybridization screening assay and by polymerase chain reaction (PCR)-based analysis, in conjunctival samples from trachoma patients and in standard urethral and cervical swabs, all of which are chlamydia- negative by standard culture or antibody-based screening assays. Importantly, we also demonstrated that culture-negative synovial tissues from RS patients similarly contain high levels of chlamydial RNA and DNA, while parallel samples from patients with other arthropathies do not. Further, preliminary evidence indicates that the nucleic acids shown in either hybridization or PCR assays are derived from viable, metabolically-active chlamydia. In this application, we describe studies to assess the prevalence and clinical consequences of inapparent chlamydial infection of the synovium in patients with/without RS. In these and related laboratory studies, we address clinical, biochemical, and molecular biological questions regarding the significance, natural history, characteristics, mechanisms of pathogenesis, and antibiotic susceptibility of such inapparent chlamydial infections. We further propose detailed molecular genetic studies to define the transcriptional and overall metabolic activity of inapparently-infecting chlamydial cells, and we describe experiments to investigate one possible mechanism for the reactivation of inapparent synovial chlamydial infection. These studies will give new insights for development of effective treatment programs for RS patients, and they will augment our understanding of an important but as yet poorly recognized facet of the chlamydial pathogenesis process.