Elucidating the Role of the Vaginal Microbiome and Daily Stress in Precancerous Cervical Lesions: A Multi-level Study.

Despite progress in human papillomavirus (HPV) vaccination uptake, about 3 million women are still diagnosed with precancerous cervical lesions each year in the US. Most spontaneously regress but yearly follow up and invasive prophylactic care (e.g., endocervical curettage and cervical biopsy) is still required as it is not clear which may progress to cervical cancer. Women with more persistent HPV infections and precancerous lesions, as well as a higher incidence of cervical cancer are disproportionately impacted by these invasive prophylactic procedures and their sequelae (e.g., pain, bleeding, scarring, infertility, future miscarriages, and preterm births). The vaginal microbiome (VMB) has been implicated in sustaining HPV infection and development of precancerous lesions. HPV-positive women, and women with precancerous lesions are more likely to have a suboptimal VMB with high taxonomic diversity with depletion of Lactobacillus species (both features of vaginal inflammation and dysbiosis) and are also associated with worse prognosis for precancerous lesions. My preliminary data shows that an optimal, Lactobacillus predominant VMB is protective against the risk of a precancerous cervical lesion for some but not all women. Since the VMB is susceptible to the host micro and macro environments, it is plausible that these differences override the protective effect of the VMB in some women. At the micro level, differences in species-specific metabolic profiles might be contributing to lesion prognosis by disturbing vaginal homeostasis. At the macro level, psychological stress, which is experienced and perceived differently across individuals, may influence the VMB through a cortisol-mediated pathway which has been biologically implicated in VMB dynamics and known to become dysregulated in some women in response to stress. In this K01 application, I will test the hypothesis that daily experiences of stress and corresponding cortisol responses drive changes in the VMB that, in turn, influence differential regression of precancerous lesions. I will measure VMB changes and psychological (ecological momentary assessments), and physiological stress (salivary cortisol) among 180 women diagnosed with a cervical lesion, assessed during the critical time between their routine pap screen and abnormal follow-up. The proposed mentorship, training and research will give me specific critical skills in bioinformatics, statistical and molecular biology to interrogate plausible mechanisms through which the VMB might underlie differential etiologies for pre-cancerous cervical lesions. The training described in this proposal will prepare me to become an independent translational investigator leading to the identification of practical solutions to improve cervical health outcomes.