Pathogensis of Chlamydial Infection

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Chlamydia trachomatis infection of oculogenital epithelial cells causes blinding trachoma and sexually transmitted disease (STD); diseases that affect hundreds of millions of people world-wide. Infection of women has serious post-infection sequalae such as pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. A pathognomonic feature of these diseases is the inability of the host to generate an adequate protective immune response resulting in multiple episodes of re-infection or persistent infection that leads to damaging inflammatory disease of unknown pathophysiology. Current public health management of trachoma and STD is based on mass drug treatment or aggressive diagnostic screening and antibiotic treatment; respectively, that unfortunately have been largely ineffective. Effective control of trachoma and chlamydial STD requires a vaccine. The overall goal of our work is to understand the pathogenic mechanisms by which chlamydia evade host defenses that allow for the establishment of chronic infection and damaging inflammatory disease. Our logic is that a better understanding of the pathobiology of chlamydial infection and disease will be important to the design of new effective vaccines for the prevention of trachoma and STD. To this end, we have used a female mouse model of urogenital tract infection and focused our investigations on the study of two chlamydial virulence factors; (i) the C. trachomatis inclusion membrane protein CT135, and (ii) the C. trachomatis plasmid. We found CT135 functions in the evasion of host innate immunity by exporting outer membrane lipoprotein, a pathogen associated molecular pattern molecule, from the chlamydial inclusion to the host cytosol. CT135 exported lipoprotein specifically targets and activates the MyD88 non-canonical inflammasome pathway of phagocytes resulting in the secretion of IL1-alpha and IL1-beta that subsequently drives damaging inflammatory oviduct pathology. Moreover, we found that the chlamydial plasmid functions in the establishment of persistent infection of the female genital tract. Plasmid gene proteins 3 and 4 were found to be essential in establishing persistent infection. Future studies will design C. trachomatis vaccine strains that have been genetically modified to mutationally inactive CT135 and cured of the plasmid. These strains will be tested as live-attenuated vaccines to prevent chlamydial STD using the mouse genital tract model.