Historically, animal modeling of gonorrhea has been hampered by the exclusive adaptation of Neisseria gonorrhoeae to humans. Genital tract infection can be established in female mice that are treated with 17β-estradiol, however, and many features of experimental murine infection mimic human infection. Here we review the colonization kinetics and host response to experimental murine gonococcal infection, including mouse strain differences and evidence that IL-17 responses, toll-like receptor 4, and T regulatory cells play a role in infection. We also discuss the strengths and limitations of the mouse system and the potential of transgenic mice to circumvent host restrictions. Additionally, we review studies with genetically defined mutants that demonstrated a role for sialyltransferase and the MtrC–MtrD–MtrE active efflux pump in evading innate defenses in vivo, but not for factors hypothesized to protect against the phagocytic respiratory burst and H2O2-producing lactobacilli. Studies using estradiol-treated mice have also revealed the existence of non-host-restricted iron sources in the female genital tract and the influence of hormonal factors on colonization kinetics and selection for opacity (Opa) protein expression. Recent work by others with estradiol-treated mice that are transgenic for human carcinoembryonic adhesion molecules (CEACAMs) supports a role for Opa proteins in enhancing cellular attachment and thus reduced shedding of N. gonorrhoeae. Finally we discuss the use of the mouse model in product testing and a recently developed gonorrhea chlamydia coinfection model.
Genital tract infections caused by Neisseria gonorrhoeae and Chlamydia trachomatis serovars D to K occur at high incidence in many areas of the world. Despite high rates of coinfection with these pathogens, investigations of host-parasite interactions have focused on each pathogen individually. We describe here a coinfection model in which female BALB/c mice were first infected with the mouse Chlamydia species C. muridarum and then inoculated with N. gonorrhoeae following treatment with water-soluble 17-estradiol to promote long-term gonococcal infection. Viable gonococci and chlamydiae were recovered for an average of 8 to 10 days, and diplococci and chlamydial inclusions were observed in lower genital tract tissue by immunohistochemical staining. Estradiol treatment reduced proinflammatory cytokine and chemokine levels in chlamydia-infected mice; however, coinfected mice had a higher percentage of vaginal neutrophils compared to mice infected with either pathogen alone. We detected no difference in pathogen-specific antibody levels due to coinfection. Interestingly, significantly more gonococci were recovered from coinfected mice compared to mice infected with N. gonorrhoeae alone. We found no evidence that C. muridarum increases gonococcal adherence to, or invasion of, immortalized murine epithelial cells. However, increased vaginal concentrations of inflammatory mediators macrophage inflammatory protein 2 and tumor necrosis factor alpha were detected in C. muridarum-infected mice prior to inoculation with N. gonorrhoeae concurrently with the downregulation of cathelicidin-related antimicrobial peptide and secretory leukocyte peptidase inhibitor genes. We conclude that female mice can be successfully infected with both C. muridarum and N. gonorrhoeae and that chlamydia-induced alterations in host innate responses may enhance gonococcal infection.Chlamydia and gonorrhea are the two most common notifiable infectious diseases in the United States, with over 1 million cases of chlamydia and 350,000 cases of gonorrhea reported to the Centers for Disease Control in 2008 (9). Actual rates of infection are much higher due to high rates of asymptomatic infection (50). As many as 50 to 70% of individuals with gonorrhea also have a chlamydial infection (20,50,55), and empirical treatment for chlamydia upon detection of N. gonorrhoeae is recommended (10,27). Neisseria gonorrhoeae and Chlamydia trachomatis are both Gram-negative, humanspecific pathogens. In symptomatic infections, both organisms elicit a proinflammatory response characterized by the influx of polymorphonuclear leukocytes (PMNs). Clinically, gonorrhea is typically more pyogenic. Postinfection complications can occur with either pathogen and complications are generally more common and more severe in women. Infections that ascend to the upper genital tract in women lead to pelvic inflammatory disease (PID), the complications of which include chronic pelvic pain, ectopic pregnancy, and infertility (28, 78).The incidence (50, 55), transmission (45,46,48), and...
The author hereby certifies that the use of any copyrighted material in the thesis manuscript entitled: "Chlamydia muridarum Alters the Immune Environment of the Murine Genital Tract to be More Permissive for Infection with Neisseria gonorrhoeae in a Novel Coinfection Model" is appropriately acknowledged and, beyond brief excerpts, is with the permission of the copyright owner.
of concurrent viral plaques. Despite rapid cell-to-cell spread of HSV-2, infected cells are eliminated by localised CD8+ T-cells within 24 h of plaque initiation. Moreover, the extent of secondary plaque formation prior to episode termination is determined by spatial CD8 + T-cell density surrounding the site of infection. Conclusions Genital HSV-2 utilises three kinetically distinct methods of spread to initiate and sustain prolonged shedding episodes. The extent and severity of secondary plaque formation is determined by spatial immune cell density.
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