the chlamydia protease cpaf regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence

• DOI: 10.17615/nnmh-5k60
• Publication Date: 2011-07-01
• Authors: Dewey G. McCafferty; Beckley K. Davis; Raphael H. Valdivia; Maria M. Bednar; Vishar Amin; Jenny P.-Y. Ting; Ine Jorgensen
• Keywords: 0301 basic medicine; Cancer Research; Cell Membrane Permeability; Virulence Factors; Molecular Sequence Data; Chlamydia trachomatis; Amino Acid Chloromethyl Ketones; Mice; 03 medical and health sciences; Bacterial Proteins; Immunology and Microbiology(all); Endopeptidases; Animals; Protease Inhibitors; Amino Acid Sequence; Molecular Biology; Bacterial Secretion Systems; Antigens, Bacterial; Cell Death; Caspase 1; Epithelial Cells; 3. Good health; Protein Transport; Host-Pathogen Interactions; Peptides

The obligate intracellular bacterial pathogen Chlamydia trachomatis injects numerous effector proteins into the epithelial cell cytoplasm to manipulate host functions important for bacterial survival. In addition, the bacterium secretes a serine protease, chlamydial protease-like activity factor (CPAF). Although several CPAF targets are reported, the significance of CPAF-mediated proteolysis is unclear due to the lack of specific CPAF inhibitors and the diversity of host targets. We report that CPAF also targets chlamydial effectors secreted early during the establishment of the pathogen-containing vacuole (“inclusion”). We designed a cell-permeable CPAF-specific inhibitory peptide and used it to determine that CPAF prevents superinfection by degrading early Chlamydia effectors translocated during entry into a pre-infected cell. Prolonged CPAF inhibition leads to loss of inclusion integrity and caspase-1-dependent death of infected epithelial cells. Thus, CPAF functions in niche protection, inclusion integrity and pathogen survival, making the development of CPAF-specific protease inhibitors an attractive anti-chlamydial therapeutic strategy.