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.

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    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.
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    ABSTRACT: Understanding the cellular populations and mechanisms responsible for overcoming immune compartmentalization is valuable for designing vaccination strategies targeting distal mucosae. In this study, we show that the human pathogen Chlamydia trachomatis infects the murine respiratory and genital mucosae and that T cells, but not Abs, elicited through intranasal immunization can protect against a subsequent transcervical challenge. Unlike the genital infection where CD8(+) T cells are primed, yet fail to confer protection, we found that intranasal priming engages both CD4(+) and CD8(+) T cells, allowing for protection against genital infection with C. trachomatis. The protection is largely dependent on IFN-γ secretion by T cells. Moreover, different chemokine receptors are critical for C. trachomatis-specific CD4(+) T cells to home to the lung, rather than the CXCR3- and CCR5-dependent migration observed during genital infection. Overall, this study demonstrates that the cross-mucosa protective immunity against genital C. trachomatis infection following intranasal immunization is not dependent on Ab response but is mediated by not only CD4(+) T cells but also by CD8(+) T cells. This study provides insights for the development of vaccines against mucosal pathogens that threaten reproductive health worldwide. Copyright © 2015 by The American Association of Immunologists, Inc.
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    ABSTRACT: Chlamydia trachomatis is an obligate intracellular epitheliatropic bacterial pathogen of humans. Infection of the eye can result in blinding trachoma, the leading cause of preventable blindness in the world. The pathophysiology of blinding trachoma is driven by multiple episodes of re-infection of conjunctival epithelial cells producing an intense chronic inflammatory response resulting in sub-mucosal tissue remodeling and scarring. Recent reports have shown that trachoma organisms lacking the cryptic chlamydial plasmid are highly attenuated for macaque eyes, a relevant experimental model of human trachoma infection. To better understand the molecular basis of plasmid-mediated infection attenuation and potential modulation of host immunity we conducted transcriptional profiling of human epithelial cells infected with C. trachomatis plasmid-bearing (A2497) and plasmid-deficient (A2497P(-)) organisms. Infection of human epithelial cells with either strain increased the expression of host genes coding for pro-inflammatory (GM-CSF, MCSF, IL6, IL8, IL1A, CXCL1, CXCL2, CXCL3, ICAM1), chemo-attraction (CCL20, CCL5, CXCL10), immune suppression (PD-L1, NFKB1B, TNFAIP3, CGB), apoptosis (CASP9, FAS, IL24), cell growth and fibrosis (EGR1 and IL20) proteins. Statistically significant increases in gene expression for many of these genes were found in A2497 infected cells compared to A2497P(-) infected cells. Our findings suggest the chlamydial plasmid plays a focal role in the cellular host-cell inflammatory response to infection and immune avoidance. These results provide new insights into the role of the chlamydial plasmid as a chlamydial virulence factor and its contributions to trachoma pathogenesis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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