Characterizing the Redoxome of Chlamydia and Its Host Cell

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Project Summary: Characterizing the Redoxome of Chlamydia and Its Host Cell Chlamydia is an obligate intracellular bacterial pathogen that causes a range of serious diseases in humans. In developed countries, Chlamydia trachomatis is the primary cause of bacterial sexually transmitted infections (STI). Indeed, recent reports from the Centers for Disease Control highlight the increasing incidence of STIs, with chlamydia infections consistently outpacing all other types. In developing countries, C. trachomatis is not only a significant cause of STI, but it is also responsible for the primary cause of infectious preventable blindness, trachoma. The major concern of chlamydial infections is that they are often asymptomatic and undiagnosed, which can lead to chronic sequelae. These include pelvic inflammatory disease, tubal factor infertility, and reactive arthritis for C. trachomatis. Consequently, chlamydial diseases remain a significant burden on health care systems around the world. In adapting to obligate intracellular growth, Chlamydia has significantly reduced its genome size and eliminated genes from various pathways as it relies on the host cell for its metabolic needs. This pathogen also alternates between different functional and morphological forms during its normal growth, also referred to as its developmental cycle. These observations, combined with its obligate intracellular dependence, makes Chlamydia a difficult organism with which to work. However, recent development of genetic tools to study chlamydiae mechanistically have significantly enhanced our understanding of this pathogen. This proposal applies a combination of these new genetic techniques and established mass spectrometry-based approaches to evaluate proteins subjected to redox regulation in both the host and bacterium. The hypothesis of the proposed work is that Chlamydia uses redox signaling to trigger secondary differentiation from the replicative to the infectious form of the organism. The major goals of this two-year funding proposal are to identify host and bacterial proteins subjected to redox regulation as a first step towards addressing our hypothesis. Selected wild-type and mutant proteins will be evaluated for changes in their redox status both in vitro and in cell culture. Results from this study will advance our understanding of this important pathogen and lead to further work to characterize the function of identified redox-regulated proteins. This may, in turn, lead to the design of novel therapeutic agents that are specific for Chlamydia. This will allow for minimal effects on normal flora for patients receiving treatment for this highly prevalent disease.