Impact of Menstruation on Chlamydial and Gonorrhea Infection

Abstract: Although vast majority and in many regions of the world, the overwhelming majority of women and adolescent girls experience periodic menstruation; how this immune-mediated tissue remodeling process compromises cellular immunity generated against sexually transmitted pathogens, including Chlamydia trachomatis (C. trachomatis) and Neisseria Gonorrhoeae (N. gonorrhoeae), is poorly understood. C. trachomatis and N. gonorrhoeae are the causative agents of the most costly and common bacterial sexually transmitted infections (STIs), with the highest incidence of C. trachomatis infections occurring in women and adolescent girls of reproductive age. Genital infections by these STI pathogens can lead to severe health complications, including congenital transmissions, ectopic pregnancies, infertility, and chronic pelvic pain. Moreover, these infections increase the risk of acquiring more severe secondary infections, including human immunodeficiency virus type- 1 (HIV-1). Taken together, these facts emphasize the critical need for an effective vaccine to prevent infections of the female reproductive tract (FRT). Memory T cells that become localized in the cervicovaginal and uterine mucosa through a recent infection or from vaccination provide optimal immune protection against bacterial STI pathogens, leading to more rapid bacterial clearance and reducing disease severity. Therefore, generating long- lived resident memory T cells in the reproductive tract mucosa that will recognize and respond against C. trachomatis and N. gonorrhoeae is a promising approach to strengthening immunity. Previous scientific research investigations into understanding tissue-resident memory T cell durability demonstrate that local environmental molecular signals can provide critical support that determines tissue-resident memory T cell development, regionalization, and prolonged viability at sites such as the lung, skin, and gut. Yet, despite the fact that genital chlamydial and gonorrheal reinfections in women are common and there is no available vaccine, we have a very limited understanding of how the tissue remodeling events of menstruation alter the reproductive tract environment to drive T cell immunity. Therefore, a major challenge for developing prophylactic strategies, including vaccines that can prevent genital chlamydia infections, is to determine how to support long-lived and durable tissue-resident memory T cells in the reproductive tract under menstrual cycle regulation. The goals of our proposal are to acquire critical insights into the mechanism(s) by which menstruation regulates immune protection and identify strategies that can support optimal memory T cell durability against chlamydial and gonococcal infections in the reproductive tract throughout this process.