Chlamydia trachomatis infections cause sexually transmitted disease (STD) and blinding trachoma; diseases that affect hundreds of millions of people world-wide. A pathognomonic feature of chlamydial infection is the failure to evoke adequate protective immunity resulting in re-infection or persistent infection. The overall goal of our work is to understand the pathogenic mechanisms by which chlamydiae evade host defenses and establish persistent infection. To this end, we have shown that the chlamydial plasmid is major virulence factor. Plasmid-free chlamydia produce attenuated self-limiting infections that generate minimal to no pathology. Notably, attenuated infection generates a robust B and T cell immunity that is protective following challenge with virulent plasmid positive organisms. To understand how the plasmid functions as a virulence factor we made deletion mutants for all 8-plasmid gene encoded proteins (pgp) and characterized the strains in in vitro and in vivo infection models. We found that pgp 1,2,5,6,7 and 8 have housekeeping functions that control plasmid replication and maintenance. In contrast, Pgp 3 and 4 were shown to be dominant virulence factors. We showed that pgp 4 is a transcriptional regulator of multiple chromosomal virulence genes that function in chlamydial exit from host cells and the establishment of persistent infection. These finding provide an explanation at the molecular level for the dominant infection attenuating phenotype of plasmid-free organisms. Thus, plasmid-free chlamydia are being investigated as live-attenuated vaccines for the prevention of STD and blinding trachoma. We are also pursuing live attenuated chlamydia carrying an engineered chlamydial plasmid with deleted virulence genes pgp3 and pgp4 capable of expressing non-chlamydial genes as a novel vaccine platform for the prevention of other important mucosal diseases.

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18
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2017
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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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