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

Producción científica: Articlerevisión exhaustiva

47 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)1095-1104
Número de páginas10
PublicaciónJournal of Infectious Diseases
Volumen207
N.º7
DOI
EstadoPublished - abr 1 2013

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

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