Infection of Human Fallopian Tube Epithelial Cells withNeisseria gonorrhoeaeProtects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis

Abstract

Following infection withThe female reproductive tract is an immunologically unique site which must respond to a diverse array of sexually transmitted pathogens and must also be tolerant to allogeneic sperm and to conceptuses. Pelvic inflammatory disease (PID) is an acute clinical syndrome associated with the ascending spread of microorganisms through the female reproductive tract (80). PID encompasses a multitude of inflammatory conditions of the upper reproductive tract organs, with the majority of proven cases of PID being caused by Chlamydia trachomatis and Neisseria gonorrhoeae (gonococcus) (32), and coinfection with both pathogens is common.Neisseria gonorrhoeae is the etiologic agent of gonorrhea, and the organism infects the mucosal epithelia of the male urethra and the lower genital tracts (vagina/cervix) of women. Localized infection with gonococci leads to a mucopurulent cervicitis in women, but it is also frequently asymptomatic. However, in approximately 10 to 25% (7,26,70) of untreated individuals, infection may ascend into the upper reproductive tract to involve the endometrium, ovaries, myometrium, parametrium, and Fallopian tubes (FT) (32, 46). The host response to this ascending infection is manifested as endometritis, pelvic (tubal or ovarian) peritonitis, tubal abscess, and salpingitis in the FT, and all of these inflammatory conditions encompass the clinical syndrome of PID. Long-term sequelae that develop in individuals presenting with PID, such as chronic pelvic pain, tubal damage, and ectopic pregnancy (7,26,70), are recognized as important public health problems worldwide (32,46).The FT is essentially a muscular organ whose lumen is lined by columnar ciliated cells and secretory cells with microvilli (68), and it plays a critical role in mammalian reproduction, functioning as a channel and storage organ for spermatozoa, a collecting vessel for oocytes released from the ovaries, the site of fertilization and zygote formation, and a means for transporting the early embryo to the uterus (54, 68). It is recognized that salpingitis induced by gonococcal infection causes significant tissue damage in the FT, which is resolved by a process of repair by infiltrating fibroblasts that leads to scarring. These events cause functional impairment of the tubes and irreversible infertility (80). However, little is known of the molecular mechanisms involved in the early stages of infection of the FT by ascending gonococci that initiate the inflammatory response. Studying the pathogenesis of gonococcus-induced salpingitis has relied on the use of ex vivo human FT organ tube

Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

“…Alternatively, bacterial pathogens could inhibit apoptosis during infection, which provides a survival benefit for the bacteria to survive and replicate inside host cells (10,21,32,38,43,55). In the present study, we have demonstrated that Salmonella-induced apoptosis at the sites of infection in mice lacking Akt2 and Akt2 deficiency renders these mice more susceptible to infection, suggesting that apoptosis may play an important role in the pathogenesis of Salmonella-induced colitis.…”

Tumour necrosis factor-α is the signal induced by mating to shutdown a 2-methoxyestradiol nongenomic action necessary to accelerate oviductal egg transport in the rat

“…TNF-a has been associated with the cell and tissue damage observed in gonococcal salpingitis (McGee et al 1992, Morales et al 2006). This damage is correlated with increased TNF-a release by epithelium cells of the human oviduct induced by gonococcal infection (McGee et al 1992).…”

“…These effects may involve a direct interaction between the cells of the female reproductive tract and the different components of the seminal plasma and/or spermatozoa to modulate the immune system resulting in cellular and molecular changes along the female reproductive tract (reviewed in Sharkey et al (2007)). Tumour necrosis factor-a (TNF-a) is a cytokine associated with immune responses in the female genital tract (Tremellen et al 1998, Maisey et al 2003, Morales et al 2006. Furthermore, transcripts of TNF-a and their receptors are expressed in mice, bovine and human oviduct (Hunt et al 1993, Srivastava et al 1996, Wijayagunawardane et al 2003, Reyes et al 2007.…”

Nitric oxide is not involved in Neisseria gonorrhoeae-induced cellular damage of human Fallopian tubes in vitro

“…However, Ngo infection induces damage to ciliated cells primarily, leading to a loss in ciliary activity and eventually to sloughing of cells from the epithelium Stephens et al, 1987]. Cell death in the FT epithelium has been shown to correlate with the up-regulated production of tumour necrosis factor (TNF)-α by the FT epithelium [McGee et al, 1992;McGee et al, 1996;Morales et al, 2006] and it is likely that gonococcal los lipooligosaccharides (LOS) and peptidoglycan fragments are key stimulators of this TNF-α release Melly et al, 1981;Melly et al, 1984]. In previous studies, we observed an apoptotic phenotype in cells of FT explant epithelium following Ngo infection and demonstrated that TNF-α mediated cell death by apoptosis in primary FT epithelial cells occurs in vitro [Morales et al, 2006].…”

“…Cell death in the FT epithelium has been shown to correlate with the up-regulated production of tumour necrosis factor (TNF)-α by the FT epithelium [McGee et al, 1992;McGee et al, 1996;Morales et al, 2006] and it is likely that gonococcal los lipooligosaccharides (LOS) and peptidoglycan fragments are key stimulators of this TNF-α release Melly et al, 1981;Melly et al, 1984]. In previous studies, we observed an apoptotic phenotype in cells of FT explant epithelium following Ngo infection and demonstrated that TNF-α mediated cell death by apoptosis in primary FT epithelial cells occurs in vitro [Morales et al, 2006]. Eventually, resolution of the inflammatory response and cell death involves a process of repair by infiltrating fibroblasts that leads to permanent scarring, eventual functional impairment of the tubes and irreversible infertility [Westrom and Wolnerhanssen, 1993].…”