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Prevention of Chlamydia-induced infertility by inhibition of local caspase activity.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2013 Apr; Vol. 207 (7), pp. 1095-104. Date of Electronic Publication: 2013 Jan 09. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Apoptosis
Caspase 1 genetics
Caspase 3 genetics
Chlamydia Infections enzymology
Chlamydia Infections microbiology
Chlamydia Infections pathology
Enzyme Activation
Female
HeLa Cells
Humans
Infertility, Female enzymology
Inflammation microbiology
Inflammation pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Pregnancy
Pregnancy Complications, Infectious enzymology
Pregnancy Complications, Infectious microbiology
Pregnancy Complications, Infectious pathology
Caspase 1 metabolism
Caspase 3 metabolism
Chlamydia trachomatis pathogenicity
Infertility, Female microbiology
Infertility, Female prevention & control
Pregnancy Complications, Infectious prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6613
- Volume :
- 207
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 23303804
- Full Text :
- https://doi.org/10.1093/infdis/jit009