Chlamydia trachomatis is an obligate intracellular bacterial pathogen that is the cause of a wide spectrum of human diseases, including blinding trachoma. Chlamydiae infect mammalian cells by attachment, endocytosis and inhibition of lysosomal fusion with endosomes containing chlamydia. 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 mediates 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 the mechanisms of infection, b) mediators of virulence and c) the development of new approaches for intervention.
The specific aims of this application will define molecular and biochemical mechanisms involved in attachment of chlamydia to host cells.
The aims are derived from new information that demonstrates a novel and essential role for glycosaminoglycan-mediated attachment of chlamydia to host cells. The hypothesis is that chlamydiae attach to mammalian host cells by a trimolecular complex in which heparan sulfate-like glycosaminoglycan bridges lectin-like receptors on chlamydia and on the host cell. A molecular understanding of attachment will provide a rational foundation for the study of other important microbiological characteristics such as uptake, inhibition of lysosomal fusion, and persistence of infection.
The specific aims are: 1)Biophysical and biochemical characterization of glycosaminoglycan- mediated attachment of chlamydiae to host cells. 2)Physical and chemical characterization of the glycosaminoglycan ligand (adhesin). 3)Identify and characterize the chlamydial glycosaminoglycan receptor. 4)Produce and characterize chlamydial attachment surrogates that contain the receptor-adhesin complex. 5)Identify and characterize the mammalian host cell glycosaminoglycan receptor.
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