Mycoplasma genitalium Rapidly Disseminates to the Upper Reproductive Tracts and Knees of Female Mice following Vaginal Inoculation

Abstract

Mycoplasma genitalium is an emerging sexually transmitted infection and in women isMycoplasma genitalium is an emerging sexually transmitted pathogen that was first identified as a cause of inflammatory urogenital disease in men (reviewed in references 15 and 18). Importantly, M. genitalium infections in women have also been associated with inflammatory syndromes, including cervicitis (8,24,27,32,50) and pelvic inflammatory disease (12), and (serologically) with impaired fertility (4, 37). Mechanistically, M. genitalium has previously been shown to activate highly expressed Toll-like receptors in reproductive tract epithelia, leading to inflammation (28,29). Collectively, these associations have led to an increased awareness of M. genitalium as a pathogen that could adversely affect reproductive health. It may also be of considerable importance that M. genitalium is strongly associated with HIV infections in men and women (reviewed in reference 31), suggesting that reproductive tract infections by M. genitalium may increase the likelihood of acquiring or transmitting other genital pathogens.Although the genital tract seems to be a preferred site of colonization, M. genitalium also has been a suspected cause of reactive arthritis, since DNA was previously detected in the knee joints of arthritic patients (45, 47) and in synovial fluid from temporomandibular joints (23). It is possible that M. genitalium may be a cause of sexually acquired reactive arthritis, but to date, no direct evidence exists for an association with an arthritic condition. Furthermore, no published reports have addressed the ability of M. genitalium to disseminate from the vagina to colonize the joint tissues or upper genital tract tissues. Similarly, there is a lack of experimental evidence for the causal associations of M. genitalium infection with inflammatory disease syndromes in women.As epidemiological data continue to implicate M. genitalium as a cause of reproductive tract disease, relevant animal models to investigate pathogenesis and evaluate therapeutic interventions are of utmost importance. Five years after the initial isolation of M. genitalium from men with urethritis (48), several large-animal species, including male cynomolgus monkeys (Macaca fascicularis), male chimpanzees (Pan troglodytes), female squirrel monkeys (Saimiri sciureus), female tamarins (Saguinus mystax), and female marmosets (Callithrix jacchus [44]), were found to be susceptible to experimental urogenital infection. These studies provided excellent preliminary evidence that M. genitalium could establish infection of female reproductive tract tissues. However, the cost of developing and maintaining primate and large-animal models prohibits experimentation employing larger-scale studies to address biological variability as part of an effective model of reproductive tract disease. In contrast, rodent models are cost-effective and afford the opportunity to investigate larger study populations of animals with specific genetic characteristics. Such models also allo...

Mycoplasma genitalium: from Chrysalis to Multicolored Butterfly

“…Thus, the treatment of female mice and hamsters with progesterone was found to be a prerequisite for the establishment of genital tract colonization with M. genitalium, which could then be maintained for several weeks (53). Treatment with estradiol failed to induce colonization, although partial effectiveness has been found by others (143). It is unknown if different animal strains, inoculum sizes, and inoculation methods could account for the divergent observations.…”

“…Further evidence for M. genitalium causing PID is (i) the ability of the organisms to adhere to Fallopian tube mucosal epithelial cells in organ culture (29) and to affect the cells and cause ciliary damage (5), (ii) the production of endometritis and salpingitis experimentally in several subhuman primate species (151,202,204) and hydrosalpinx formation in mice (143), (iii) the association of tubal factor infertility with a previous infection with M. genitalium (25), and (iv) the demonstration of M. genitalium antibody responses in one-third of women with acute PID (150), a finding disputed by some investigators (110,123). In summary, the overall supportive aspects have led to the conclusion that M. genitalium is one of the causes of PID (62).…”

Serine-Rich Repeat Proteins and Pili Promote Streptococcus agalactiae Colonization of the Vaginal Tract

“…However, murine models of bacterial persistence in the cervicovaginal tract have previously yielded useful results and allow a study of microbe-host interactions in a more representative environment. A similar model of vaginal colonization and infection has been used to demonstrate the susceptibility of female mice to multiple microbes, including Neisseria gonorrhoeae (17), Chlamydia (55), Mycoplasma genitalium (24), Escherichia coli (33), Candida albicans (40), herpes simplex virus 2 (32), Trichomonas vaginalis (11), and Tritrichomonas foetus (1). We have adapted this in vivo model to study GBS vaginal colonization in the presence of native microflora.…”

“…Our in vitro data suggest that Srr-1 and PilA contribute to GBS cervicovaginal attachment. To test this ability in vivo, we developed a mouse model of GBS vaginal colonization using procedures similar to those described previously (5,17,24,32,40,55,63). Because bacterial colonization of the mouse vaginal vault is believed to be greater at estrus (5, 26), we synchronized the estral cycles of all mice using ␤-estradiol valerate.…”

Mycoplasma genitalium Infection Is Associated with Microscopic Signs of Cervical Inflammation in Liquid Cytology Specimens

“…Despite solid evidence for this organism as a cause of male nongonococcal urethritis (NGU), additional studies are needed to unequivocally implicate M. genitalium as a cause of cervicitis and other female re-productive tract syndromes. M. genitalium has a remarkable ability to establish chronic infections of the lower genital tract (13)(14)(15)(16) in lieu of strong antibody responses to at least two outer membrane antigens (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). The data regarding M. genitalium as a cause of cervicitis have been conflicting, with approximately half of published studies showing significant associations (28).…”