title: Prevention of Chlamydia-induced infertility by inhibition of local caspase activity.
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.
authors.affiliation: National Center for Emerging Zoonotic and Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA. jigietseme@cdc.gov
authors.forename: Joseph U
authors.initials: JU
authors.lastname: Igietseme
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Omosun
authors.forename: James
authors.initials: J
authors.lastname: Partin
authors.forename: Jason
authors.initials: J
authors.lastname: Goldstein
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Kahaliah
authors.initials: K
authors.lastname: Joseph
authors.forename: Debra
authors.initials: D
authors.lastname: Ellerson
authors.forename: Uzma
authors.initials: U
authors.lastname: Ansari
authors.forename: Francis O
authors.initials: FO
authors.lastname: Eko
authors.forename: Claudiu
authors.initials: C
authors.lastname: Bandea
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhong
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Black
mesh_terms: D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002690:Chlamydia Infections / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D002692:Chlamydia trachomatis / Q000472:pathogenicity*; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007247:Infertility, Female / Q000201:enzymology / Q000382:microbiology* / Q000517:prevention & control*; D007249:Inflammation / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000201:enzymology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C505409:Casp3 protein, mouse; D053148:Caspase 3; D020170:Caspase 1