Tumor necrosis factor alpha production from CD8+ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum infection.

South Texas Center for Emerging Infectious Diseases, Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA.
Infection and immunity (Impact Factor: 4.16). 07/2011; 79(7):2928-35. DOI: 10.1128/IAI.05022-11
Source: PubMed

ABSTRACT The immunopathogenesis of Chlamydia trachomatis-induced oviduct pathological sequelae is not well understood. Mice genetically deficient in perforin (perforin(-/-) mice) or tumor necrosis factor alpha (TNF-α) production (TNF-α(-/-) mice) displayed comparable vaginal chlamydial clearance rates but significantly reduced oviduct pathology (hydrosalpinx) compared to that of wild-type mice. Since both perforin and TNF-α are effector mechanisms of CD8(+) T cells, we evaluated the role of CD8(+) T cells during genital Chlamydia muridarum infection and oviduct sequelae. Following vaginal chlamydial challenge, (i) mice deficient in TAP I (and therefore the major histocompatibility complex [MHC] I pathway and CD8(+) T cells), (ii) wild-type mice depleted of CD8(+) T cells, and (iii) mice genetically deficient in CD8 (CD8(-/-) mice) all displayed similar levels of vaginal chlamydial clearance but significantly reduced hydrosalpinx, compared to those of wild-type C57BL/6 mice, suggesting a role for CD8(+) T cells in chlamydial pathogenesis. Repletion of CD8(-/-) mice with wild-type or perforin(-/-), but not TNF-α(-/-), CD8(+) T cells at the time of challenge restored hydrosalpinx to levels observed in wild-type C57BL/6 mice, suggesting that TNF-α production from CD8(+) T cells is important for pathogenesis. Additionally, repletion of TNF-α(-/-) mice with TNF-α(+/+) CD8(+) T cells significantly enhanced the incidence of hydrosalpinx and oviduct dilatation compared to those of TNF-α(-/-) mice but not to the levels found in wild-type mice, suggesting that TNF-α production from CD8(+) T cells and non-CD8(+) cells cooperates to induce optimal oviduct pathology following genital chlamydial infection. These results provide compelling new evidence supporting the contribution of CD8(+) T cells and TNF-α production to Chlamydia-induced reproductive tract sequelae.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydrosalpinx is a pathological hallmark for tubal infertility associated with chlamydial infection. However, the mechanisms of hydrosalpinx remain unknown. Here, we report that complement factor 5 (C5) contributes significantly to chlamydial induction of hydrosalpinx. Mice lacking C5 (C5-/-) failed to develop any hydrosalpinx while ∼42% of the corresponding wild type mice (C5+/+) did so following an intravaginal infection with C. muridarum. Surprisingly, deficiency in C3 (C3-/-), an upstream component of the complement system, did not affect mouse susceptibility to chlamydial induction of hydrosalpinx. Interestingly, C5 activation was induced by chlamydial infection in oviduct of C3-/- mice, explaining why the C3-/- mice remained susceptible to chlamydial induction of hydrosalpinx. Similar levels of live chlamydial organisms were recovered from oviduct tissues of both C5-/- and C5+/+ mice, suggesting that C5 deficiency did not affect C. muridarum ascending infection. Furthermore, C5-/- mice were still more resistant to hydrosalpinx induction than C5+/+ mice even when live C. muridarum organisms were directly delivered into the upper genital tract, both confirming the role of C5 in promoting hydrosalpinx and indicating that the C5-facilitated hydrosalpinx was not due to enhancement of ascending infection. The C5-/- mice displayed significantly reduced lumenal inflammatory infiltration and cytokine production in oviduct tissue, suggesting that C5 may contribute to chlamydial induction of hydrosalpinx by enhancing inflammatory responses.
    Infection and Immunity 05/2014; · 4.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In women, Chlamydia trachomatis can ascend from the cervix to the Fallopian tubes where an overly aggressive host inflammatory response can cause scarring that leads to chronic pelvic pain, infertility, or ectopic pregnancy. Although screening and treatment programs for women have resulted in decreased rates of sequelae, morbidities associated with oviduct scarring continue to occur. Since corticosteroids possess anti-inflammatory and anti-fibrotic effects, we tested the ability of dexamethasone to inhibit inflammation and prevent oviduct scarring in mice genitally infected with Chlamydia muridarum. Administration of 1 or 2.5 mg/kg of dexamethasone on days 7-21 of infection resulted in reduced accumulation of inflammatory cells in the oviducts when compared to controls. However, a concomitant increase in bacterial burden was observed and chronic oviduct disease was not reduced. Adjunctive administration of a prolonged (21 days) or short course (3 days) of dexamethasone in combination with the antibiotic doxycycline also failed to reduce chronic oviduct pathology when compared to antibiotic treatment alone. Steroids administered alone or adjunctively with antibiotics failed to prevent oviduct damage in the murine model of C. trachomatis infection.
    Clinical and vaccine Immunology: CVI 04/2014; · 2.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydrosalpinx induction by C. muridarum infection in mice, a model that has been used for studying C. trachomatis pathogenesis in women, is known to depend on the cryptic plasmid that encodes 8 genes designated as pgp1-8. To identify the plasmid-encoded pathogenic determinants, we evaluated C. muridarum transformants deficient in plasmid-encoded genes pgp3, 4 or 7 for induction of hydrosalpinx. The C. muridarum transformants with in-frame deletion of either pgp3 or 4 but not 7 failed to induce hydrosalpinx. The deletion mutant phenotype was reproduced using transformants with premature termination codon insertion in the corresponding pgp genes (for minimizing 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 the lack of Pgp3 may be responsible for the attenuation in C. muridarum pathogenicity described above. The attenuated pathogenicity was further correlated with 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 for C. muridarum pathogenesis in mice.
    Infection and Immunity 10/2014; · 4.16 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014