Prevention of chlamydia-induced infertility by inhibition of local caspase activity

Joseph U. Igietseme, Yusuf Omosun, James Partin, Jason Goldstein, Qing He, Kahaliah Joseph, Debra Ellerson, Uzma Ansari, Francis O. Eko, Claudiu Bandea, Guangming Zhong, Carolyn M. Black

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Tubal factor infertility (TFI) represents 36% of female infertility and genital infection by Chlamydia trachomatis (C. trachomatis) is a major cause. Although TFI is associated with host inflammatory responses to bacterial components, the molecular pathogenesis of Chlamydia-induced infertility remains poorly understood. We investigated the hypothesis that activation of specific cysteine proteases, the caspases, during C. trachomatis genital infection causes the disruption of key fertility-promoting molecules required for embryo development and implantation. We analyzed the effect of caspase inhibition on infertility and the integrity of Dicer, a caspase-sensitive, fertility-promoting ribonuclease III enzyme, and key micro-RNAs in the reproductive system. Genital infection with the inflammation- and caspase-inducing, wild-type C. trachomatis serovar L2 led to infertility, but the noninflammation-inducing, plasmid-free strain did not. We confirmed that caspase-mediated apoptotic tissue destruction may contribute to chlamydial pathogenesis. Caspase-1 or -3 deficiency, or local administration of the pan caspase inhibitor, Z-VAD-FMK into normal mice protected against Chlamydia-induced infertility. Finally, the oviducts of infected infertile mice showed evidence of caspase-mediated cleavage inactivation of Dicer and alteration in critical miRNAs that regulate growth, differentiation, and development, including mir-21. These results provide new insight into the molecular pathogenesis of TFI with significant implications for new strategies for treatment and prevention of chlamydial complications.

Original languageEnglish (US)
Pages (from-to)1095-1104
Number of pages10
JournalJournal of Infectious Diseases
Volume207
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • Chlamydia
  • Dicer
  • caspase
  • infertility and pathogenesis
  • inflammasome
  • miRNAs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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    Igietseme, J. U., Omosun, Y., Partin, J., Goldstein, J., He, Q., Joseph, K., Ellerson, D., Ansari, U., Eko, F. O., Bandea, C., Zhong, G., & Black, C. M. (2013). Prevention of chlamydia-induced infertility by inhibition of local caspase activity. Journal of Infectious Diseases, 207(7), 1095-1104. https://doi.org/10.1093/infdis/jit009