Ascending Reproductive Tract Infection in Pig-Tailed Macaques Inoculated with Mycoplasma genitalium

Mycoplasma genitalium is a sexually transmitted bacterial pathogen that causes urogenital disease in men and women. M. genitalium infections can persist for months to years and can ascend to the upper reproductive tract in women where it is associated with serious sequelae including pelvic inflammatory disease, tubal factor infertility, and preterm birth. An animal model is needed to understand immune evasion strategies that allow persistence, mechanisms of ascending infection, and factors associated with clearance. ABSTRACT Mycoplasma genitalium is a sexually transmitted bacterial pathogen that causes urogenital disease in men and women. M. genitalium infections can persist for months to years and can ascend to the upper reproductive tract in women where it is associated with serious sequelae including pelvic inflammatory disease, tubal factor infertility, and preterm birth. An animal model is needed to understand immune evasion strategies that allow persistence, mechanisms of ascending infection, and factors associated with clearance. In earlier studies, we determined that pig-tailed macaques are susceptible to cervical infection; however, not all primates were successfully infected, persistence varied between animals, and ascension to the upper reproductive tract was not observed after 4 or 8 weeks of follow-up. Building on our previous findings, we refined our inoculation methods to increase infection rates, extended observation to 18 weeks, and comprehensively sampled the upper reproductive tract to detect ascending infection. With these improvements, we established infection in all (3/3) primates inoculated with M. genitalium and demonstrated lower tract persistence for 16 to 18 weeks. Ascension to the upper reproductive tract at endpoint was observed in two out of three primates. All three primates developed serum and local antibodies reacting primarily to the MgpB and MgpC adherence proteins. Elevated genital polymorphonuclear leukocytes (PMNs) and inflammatory cytokines and chemokines, erythema of the ectocervix in one primate, and histologic evidence of vaginitis and endocervicitis in two primates suggest a mild to moderate inflammatory response to infection. This model will be valuable to understand the natural history of M. genitalium infection including mechanisms of persistence, immune evasion, and ascension to the upper reproductive tract.