The impact of the commensal vaginal microbiome on resident memory T cell differentiation and function

Brown University, Providence RI

Investigators

Abstract

Project Summary Every day, there are more than 1 million new cases of sexually transmitted infections (STIs) worldwide that can have long-term health consequences, including infertility and pregnancy complications. For women, the vaginal microbiome has emerged as an important factor in STI acquisition and recurrence, but the mechanisms by which the microbiome influences this process is not well understood. Bacterial vaginosis (BV) occurs when the vaginal microbiome becomes dysregulated and imbalanced due to an overgrowth of anaerobes. Among women below the age of 50, this is one of the most common vaginal conditions that increases susceptibility to reproductive tract infections. Studies on how these anaerobes interact with the local immune system have mostly been focused on innate immune cells. BV-associated bacteria’s impact on CD8 T cell mediated responses and resident memory T cell differentiation and function remain unexplored. My long-term goal is to determine the role of commensal and dysbiotic bacteria on CD8 tissue resident memory T (TRM) cell immunity within the female reproductive tract (FRT). Previous studies on BV and innate immune cells have shown that bacterial metabolites from BV-associated bacteria lead to a state of chronic inflammation, partially mediated by their actions on local epithelium and the release of damage-associated cytokines. Based on this, I hypothesize that the inflammatory cytokines produced by these anaerobic bacteria will alter the differentiation of TRMs and enhance their pro- inflammatory function. To test this hypothesis, I will use a combination of in vitro and in vivo models mimicking human BV in mice to characterize the tripartite interaction between the microbiome, the vaginal epithelium, and CD8 TRMs. In aim-1, I will evaluate the impact of vaginal microbial metabolites on CD8 T cell function using a novel vaginal epithelial organoid (VEO) and T cell co-culture system. In aim-2, I will test the contribution of these vaginal microbial metabolites in vivo via either metabolite supplementation or direct engraftment of bacteria into the FRT of mice. Understanding CD8 TRM interactions with the vaginal microbiome will be instrumental in developing therapies to reduce STI transmission and pregnancy complications and improve overall reproductive health. In preparation for this proposed work, my training is being overseen by my mentor Dr. Beura, who takes an active role in developing my immunological techniques, critical thinking skills, and independent experimentation through regular one-on-one meetings. I am also supported by my co-sponsor, Dr. Laurent Brossay, and the oversight of the Brown University Pathobiology training program allowing me plentiful opportunities to engage the scientific community and broader public to improve my scientific communication skills. Completion of this proposal will equip me with the necessary attributes and key foundational knowledge to pursue a successful career as an independent researcher in the field of viral infection and immunology.