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 muramyl dipeptide (MDP), a pathogen associated molecular pattern molecule, from the chlamydial inclusion to the host cytosol. CT135 exported MDP specifically targets and activates the NOD2 non-canonical inflammasome pathway of phagocytes resulting in the secretion of IL1- and IL1- that drive damaging inflammatory oviduct pathology. Moreover, we found that the chlamydial plasmid functions in the establishment of chronic infection of the female genital tract. Plasmid gene proteins 3 and 4 were found to be essential in establishing chronic 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.

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19
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2018
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Patton, Michael John; Chen, Chih-Yu; Yang, Chunfu et al. (2018) Plasmid Negative Regulation of CPAF Expression Is Pgp4 Independent and Restricted to Invasive Chlamydia trachomatis Biovars. MBio 9:
Patton, Dorothy L; Sweeney, Yvonne C; Baldessari, Audrey E et al. (2018) The Chlamydia trachomatis Plasmid and CT135 Virulence Factors Are Not Essential for Genital Tract Infection or Pathology in Female Pig-Tailed Macaques. Infect Immun 86:
Yang, Chunfu; Kari, Laszlo; Sturdevant, Gail L et al. (2017) Chlamydia trachomatis ChxR is a transcriptional regulator of virulence factors that function in in vivo host-pathogen interactions. Pathog Dis 75:
Yang, Chunfu; Whitmire, William M; Sturdevant, Gail L et al. (2017) Infection of Hysterectomized Mice with Chlamydia muridarum and Chlamydia trachomatis. Infect Immun 85:
Patton, Michael John; McCorrister, Stuart; Grant, Chris et al. (2016) Chlamydial Protease-Like Activity Factor and Type III Secreted Effectors Cooperate in Inhibition of p65 Nuclear Translocation. MBio 7:
Porcella, Stephen F; Carlson, John H; Sturdevant, Daniel E et al. (2015) Transcriptional profiling of human epithelial cells infected with plasmid-bearing and plasmid-deficient Chlamydia trachomatis. Infect Immun 83:534-43
Song, Lihua; Carlson, John H; Zhou, Bing et al. (2014) Plasmid-mediated transformation tropism of chlamydial biovars. Pathog Dis 70:189-93
Bao, Xiaofeng; Gylfe, Asa; Sturdevant, Gail L et al. (2014) Benzylidene acylhydrazides inhibit chlamydial growth in a type III secretion- and iron chelation-independent manner. J Bacteriol 196:2989-3001
Sturdevant, Gail L; Caldwell, Harlan D (2014) Innate immunity is sufficient for the clearance of Chlamydia trachomatis from the female mouse genital tract. Pathog Dis 72:70-3
Kari, Laszlo; Southern, Timothy R; Downey, Carey J et al. (2014) Chlamydia trachomatis polymorphic membrane protein D is a virulence factor involved in early host-cell interactions. Infect Immun 82:2756-62

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