Plasmid-Encoded Pgp5 Is a Significant Contributor to Chlamydia muridarum Induction of Hydrosalpinx

Abstract

We have previously shown that the plasmid-encoded Pgp3 is a major virulence factor for C. muridarum induction of hydrosalpinx. We now report that Pgp5 also plays a significant role in the development of hydrosalpinx following C. muridarum induction. Pgp5 deficiency was introduced via either in-frame deletion (CM-Δpgp5) or premature stop codon installation (CM-pgp5S). Mice infected with either CM-Δpgp5 or CM-pgp5S developed hydrosalpinges at significantly reduced levels with an incidence rate of <40% and a mean severity score of 2 or less. In contrast, 80% or more mice developed hydrosalpinx with a severity score of >3 when mice were infected with Pgp5-sufficient C. muridarum (plasmid-competent wild type or plasmid-free C. muridarum transformed with a full plasmid or depleted of pgp7 gene). The attenuated pathogenicity of the Pgp5-deficient C. muridarum correlated with a significantly reduced level of ascending infection in the oviduct tissue despite the similar overall shedding courses between mice infected with Pgp5-deficeint versus sufficient C. muridarum. Furthermore, in the oviducts of mice infected with Pgp5-deficient C. muridarum, significantly lower levels of inflammatory cell infiltration and cytokine production were detected. Thus, Pgp5 is a significant plasmid-encoded virulence factor for C. muridarum pathogenicity in the upper genital tract.

Chlamydial Plasmid-Dependent Pathogenicity

“…The success in transforming C. muridarum [19] further enabled the evaluation of the plasmid-encoded pGPs in a female mouse hydrosalpinx/infertility induction model [79–81]. C. muridarum deficient in pGP3 either by deletion of the pgp3 gene or installation of a premature stop codon in the start region of the gene largely phenocopied the plasmid-free C. muridarum [20] although deficiency in pGP5 also reduced C. muridarum pathogenicity [82]. The failure of the pGP3-deficient C. muridarum to induce hydrosalpinx correlates with its reduced ascension to, decreased survival and attenuated induction of inflammatory infiltration in the oviduct [20].…”

“…The C. trachomatis pgp5 was as competent as C. muridarum pgp5 in suppressing the expression of the plasmid-dependent genes during C. muridarum infection, demonstrating that inhibition of the plasmid-dependent chromosomal genes is a common property of Pgp5 protein from different chlamydial species. More importantly, when pGP5-deficient C. muridarum was evaluated in mice, it displayed a partial but significant attenuation in inducing hydrosalpinx [82], suggesting that pGP5 also contributes to chlamydial pathogenicity in the mouse upper genital tract although not as robust as Pgp3 [20]. The challenge questions are how pGP5 regulates its target gene expression in chlamydial chromosome and whether the attenuated pathogenicity is caused by the increased expression of the chromosomal genes.…”

Distinct Roles of Chromosome- versus Plasmid-Encoded Genital Tract Virulence Factors in Promoting Chlamydia muridarum Colonization in the Gastrointestinal Tract

“…We have previously demonstrated that C. muridarum clones carrying mutations in the chromosomal gene tc0237 and/or tc0668 or plasmid gene pgp3 are significantly attenuated in inducing hydrosalpinx in the mouse upper genital tract (26)(27)(28)(29)(30). Thus, the C. muridarum chromosomal gene-encoded TC0237/TC0668 and plasmid-encoded pGP3 have been defined as genital tract virulence factors (23,31).…”

The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia muridarum

“…Development of a C. trachomatis plasmid manipulation system and a transformation system for C. muridarum helped to reveal that plasmid-encoded Pgp3 and Pgp5 are crucial for C. muridarum induction of upper genital tract disease (17,18). Deficiency in Pgp3 or Pgp5 results in reduced ascending infection to and chronic inflammatory infiltration in the upper genital tract.…”