Plasmid CDS5 Influences Infectivity and Virulence in a Mouse Model of Chlamydia trachomatis Urogenital Infection

Ramsey, Kyle H.; Schripsema, Justin H.; Smith, Bennett; Wang, Y.; Jham, Bruno Correia; OʼHagan, K. P.; Thomson, Nicholas R.; Murthy, Ashlesh K.; Skilton, Rachel J.; Chu, Pinpin; Clarke, Ian N.

doi:10.1128/iai.01795-14

Cited by 35 publications

(40 citation statements)

References 40 publications

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“…Third, Pgp3 forms a stable trimer (45) with a C-terminal trimerization domain similar to the receptor binding domain of tumor necrosis factor alpha (TNF-␣) (46), which suggests that Pgp3 is poised to interact with host inflammatory responses. Finally, Pgp3-deficient C. trachomatis serovar L2 is attenuated in infecting the mouse genital tract and inducing inflammatory responses (29).…”

Section: Figmentioning

confidence: 99%

“…In contrast, deficiencies in Pgp3, -5, or -7 did not significantly affect the expression of other chlamydial genes. Ramsey et al (29) recently evaluated an L2 organism with a pgp3 gene deletion in the mouse model and found that the Pgp3 deficiency significantly attenuated L2 infectivity and pathogenicity in the mouse genital tract. However, because of the failure of the wild-type L2 organisms to induce hydrosalpinx in mice, it remains unclear whether Pgp3 or any other plasmid-encoded factors are required for chlamydial induction of the longlasting hydrosalpinx (11,30) that is most relevant to C. trachomatis-induced tubal factor infertility in women (31).…”

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Plasmid-Encoded Pgp3 Is a Major Virulence Factor for Chlamydia muridarum To Induce Hydrosalpinx in Mice

et al. 2014

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dHydrosalpinx induction in mice by Chlamydia muridarum infection, a model that has been used to study C. trachomatis pathogenesis in women, is known to depend on the cryptic plasmid that encodes eight genes designated pgp1 to pgp8. To identify the plasmid-encoded pathogenic determinants, we evaluated C. muridarum transformants deficient in the plasmid-borne gene pgp3, -4, or -7 for induction of hydrosalpinx. C. muridarum transformants with an in-frame deletion of either pgp3 or -4 but not -7 failed to induce hydrosalpinx. The deletion mutant phenotype was reproduced by using transformants with premature termination codon insertions in the corresponding pgp genes (to minimize polar effects inherent in the deletion mutants). Pgp4 is known to regulate pgp3 expression, while lack of Pgp3 does not significantly affect Pgp4 function. Thus, we conclude that Pgp3 is an effector virulence factor and that lack of Pgp3 may be responsible for the attenuation in C. muridarum pathogenicity described above. This attenuated pathogenicity was further correlated with a rapid decrease in chlamydial survival in the lower genital tract and reduced ascension to the upper genital tract in mice infected with C. muridarum deficient in Pgp3 but not Pgp7. The Pgp3-deficient C. muridarum organisms were also less invasive when delivered directly to the oviduct on day 7 after inoculation. These observations demonstrate that plasmid-encoded Pgp3 is required for C. muridarum survival in the mouse genital tract and represents a major virulence factor in C. muridarum pathogenesis in mice.

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Section: Figmentioning

confidence: 99%

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Plasmid-Encoded Pgp3 Is a Major Virulence Factor for Chlamydia muridarum To Induce Hydrosalpinx in Mice

et al. 2014

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“…It remains unknown how C. trachomatis establishes a successful initial infection in the lower genital tract and achieves ascending infection. The mouse genital tract infection model has been used with either C. trachomatis (3)(4)(5)(6)(7) or C. muridarum (8)(9)(10)(11)(12)(13)(14)(15) for studying chlamydial pathogenesis and immunity. C. trachomatis infection in the mouse genital tract, unlike C. muridarum infection, often fails to induce a long-lasting upper genital tract pathology such as hydrosalpinx.…”

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The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

et al. 2016

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dDespite the extensive in vitro characterization of CPAF (chlamydial protease/proteasome-like activity factor), its role in chlamydial infection and pathogenesis remains unclear. We now report that a Chlamydia trachomatis strain deficient in expression of CPAF (L2-17) is no longer able to establish a successful infection in the mouse lower genital tract following an intravaginal inoculation. The L2-17 organisms were cleared from the mouse lower genital tract within a few days, while a CPAF-sufficient C. trachomatis strain (L2-5) survived in the lower genital tract for more than 3 weeks. However, both the L2-17 and L2-5 organisms maintained robust infection courses that lasted up to 4 weeks when they were directly delivered into the mouse upper genital tract. The CPAF-dependent chlamydial survival in the lower genital tract was confirmed in multiple strains of mice. Thus, we have demonstrated a critical role of CPAF in promoting C. trachomatis survival in the mouse lower genital tracts. It will be interesting to further investigate the mechanisms of the CPAF-dependent chlamydial pathogenicity.

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“…The recent success in transforming Chlamydia (26,(31)(32)(33)36) should facilitate the identification of the plasmid-dependent virulence factors. Indeed, the plasmid-encoded Pgp3, an immunodominant (37), trimeric (38,39), and secretion (14) protein, has been shown to play a significant role in C. trachomatis L2 infection of the mouse genital tract (40) and C. muridarum induction of hydrosalpinx (41).…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Infection with Plasmid-Free Chlamydia muridarum Reveals a Critical Role of the Plasmid in Chlamydial Ascension and Establishes a Model for Evaluating Plasmid-Independent Pathogenicity

et al. 2015

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Intravaginal infection with plasmid-competent but not plasmid-free Chlamydia muridarum induces hydrosalpinx in mouse upper genital tract, indicating a critical role of the plasmid in chlamydial pathogenicity. To evaluate the contribution of the plasmid to chlamydial ascension and activation of tubal inflammation, we delivered plasmid-free C. muridarum directly into the endometrium by intrauterine inoculation. We found that three of the six mouse strains tested, including CBA/J, C3H/HeJ, and C57BL/6J, developed significant hydrosalpinges when 1 ؋ 10 7 inclusion-forming units (IFU) of plasmid-free C. muridarum were intrauterinally inoculated. Even when the inoculum was reduced to 1 ؋ 10 4 IFU, the CBA/J mice still developed robust hydrosalpinx. The hydrosalpinx development in CBA/J mice correlated with increased organism ascension to the oviduct following the intrauterine inoculation. The CBA/J mice intravaginally infected with the same plasmid-free C. muridarum strain displayed reduced ascending infection and failed to develop hydrosalpinx. These observations have demonstrated a critical role of the plasmid in chlamydial ascending infection. The intrauterine inoculation of the CBA/J mice with plasmid-free C. muridarum not only resulted in more infection in the oviduct but also stimulated more inflammatory infiltration and cytokine production in the oviduct than the intravaginal inoculation, suggesting that the oviduct inflammation can be induced by plasmid-independent factors, which makes the hydrosalpinx induction in CBA/J mice by intrauterine infection with plasmid-free C. muridarum a suitable model for investigating plasmid-independent pathogenic mechanisms.H ydrosalpinx can be induced by lower genital tract (LGT) infection with either Chlamydia trachomatis in women or Chlamydia muridarum in mice, leading to tubal factor infertility in both women (1, 2) and mice (3, 4). Thus, intravaginal inoculation of mice with C. muridarum has been used to study the mechanisms of C. trachomatis pathogenesis and immunity (3, 5-7). We recently optimized the C. muridarum mouse model by visually detecting long-lasting hydrosalpinges 8 weeks after infection (8-12). The C. muridarum murine model-based studies have led us to hypothesize that both adequate ascension to and induction of the appropriate inflammatory responses in the upper genital tract (UGT) are necessary for hydrosalpinx development. However, the virulence factors required for the C. muridarum pathogenicity that lead to tissue inflammation and pathology have not been identified.C. trachomatis contains a highly conserved plasmid containing 8 open reading frames designated plasmid-encoded glycoprotein 1 to 8 (Pgp1 to -8, respectively) (13-16). This plasmid may play a significant role in C. trachomatis pathogenesis since plasmid-free C. trachomatis exhibited significantly reduced pathogenicity in ocular tissues of primates (17) and genital tract tissues of mice (18). These findings are consistent with a previous observation that induction of hydrosalpinx in mice by int...

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Plasmid CDS5 Influences Infectivity and Virulence in a Mouse Model of Chlamydia trachomatis Urogenital Infection

Cited by 35 publications

References 40 publications

Plasmid-Encoded Pgp3 Is a Major Virulence Factor for Chlamydia muridarum To Induce Hydrosalpinx in Mice

Plasmid-Encoded Pgp3 Is a Major Virulence Factor for Chlamydia muridarum To Induce Hydrosalpinx in Mice

The Chlamydia-Secreted Protease CPAF Promotes Chlamydial Survival in the Mouse Lower Genital Tract

Intrauterine Infection with Plasmid-Free Chlamydia muridarum Reveals a Critical Role of the Plasmid in Chlamydial Ascension and Establishes a Model for Evaluating Plasmid-Independent Pathogenicity

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