Chlamydia trachomatis is an obligate intracellular bacterial pathogen that is the cause of a wide spectrum of human diseases, including sexually transmitted diseases and blinding trachoma. Chlamydiae infect mammalian cells by attachment, endocytosis and inhibition of lysosomal fusion with endosomes containing chlamydiae. The target host cell in vivo is typically the columnar epithelial cell, and the primary mode of entry of chlamydiae into these 'non-professional phagocytic' cells is thought to be receptor-mediated endocytosis. Immunopathology caused from repeated and persistent infection causes the most severe disease outcomes; however, little is known about the molecular mechanism of chlamydial infection of host cells. The long-term objective is to understand chlamydial pathogenesis and virulence in the context of the interaction of chlamydiae with their host cells. This will yield important fundamental information for a) understanding mechanisms of infection, b) mediators of virulence and c) the development of new approaches for intervention.
The specific aims of this application will be to advance our studies to define molecular and biochemical mechanisms involved in chlamydial-specific interactions with mammalian host cells.
The aims are derived from our data that demonstrate a novel and essential role for glycosaminoglycan mediated chlamydial invasion of eukaryotic cells. The hypothesis is that chlamydiae invade mammalian host cells by a heparan sulfate-like ligand and elicit responses by the host cell which have consequences for pathogenesis. The significance of these studies is an understanding of fundamental mechanisms of chlamydial pathogenesis and virulence as an active interplay between chlamydia and its host cell.
The specific aims are: 1) Molecular characterization of the heparan sulfate-like invasin, 2) Identify and characterize the mammalian host cell chlamydial receptor, 3) Characterize the modification of host cell signal-transduction and regulatory pathways by chlamydiae, and 4) Test the protein expression and significance of chlamydia-induced changes in host cell gene transcription.
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