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 plasmid, and (ii) the C. trachomatis inclusion membrane protein CT135. We found the plasmid gene protein Pgp3 is required to establish persistent infection of the mouse female genital tract. We further identified the pathogenic mechanism of Pgp3 as an inhibitor of innate immunity anti-microbial peptides. We found that CT135 is essential for establishing continuous infection of uterine epithelial cells by killing luminal neutrophils by activating the NLRP3 inflammosome. CT135 was shown to function in inflammosome activation by exporting chlamydial outer membrane lipoprotein fragments generated during abortive chlamydial infection of neutrophils. Exported chlamydial lipoprotein fragments bound inclusion membrane associated TLR2 resulting in MyD88 signaling and activation of the NLRP3 inflammosome. This processes resulted in neutrophil death and secretion of IL1-beta. We conclude from these findings that CT135 functions to evade neutrophil host defense. Interestingly, this host defense mechanism conjointly drives genital tract myeloid mediated immunopathology. 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 female mouse genital tract model.