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

The Journal of infectious diseases 2013 Apr

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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.

Citation

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. Prevention of Chlamydia-induced infertility by inhibition of local caspase activity. The Journal of infectious diseases. 2013 Apr;207(7):1095-104