The role of the female and male reproductive microenvironment in fertility fitness

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One in eight couples are impacted by infertility, defined as difficulty obtaining or sustaining a pregnancy after one year of unprotected intercourse, and many couples turn to costly assisted reproductive technologies such as in vitro fertilization (IVF). Even with genetic screening of embryos for chromosomal abnormalities, up to 40% of embryo transfers are still unsuccessful. The lack of comprehensive mucosal systems-level data with well described implantation and both female and male fertility endpoints in the context of IVF has limited our understanding of potential microbiome, immune and intra-partner interactions that may contribute to infertility and treatment success, which has limited therapeutic options. Therefore, identifying host-microbial interactions in both female and male partners and potential intra-couple signatures of infertility could lead to novel therapeutic targets or predictive models to increase clinical pregnancy rates, which would be a significant advance. Our global hypothesis is that dysbiotic ecology and function of urogenital microbiomes drive host inflammatory processes that contribute to female and male factor infertility. In this proposal we will investigate the microbiome and immune drivers of male and female infertility by utilizing a partnered cohort with well-defined infertility and pregnancy endpoints to characterize the endometrial, cervicovaginal, seminal and penile factors contributing to IVF success. We will collect endometrial and cervicovaginal samples from the female partner during an endometrial receptivity assay (ERA) cycle which mimics the hormonal conditions present during subsequent embryo transfer cycles. A unique feature of this cohort is targeted enrollment of couples with either female or male fertility issues, providing the ability to assess fertility interactions at a per couple level. We will utilize a state-of-the-art systems biology approach including high dimensional flow cytometry with computational analysis, single cell RNA sequencing, metaproteomics, metabolomics, and host cellular analysis coupled with advanced multivariate modeling techniques to determine the effect of the female and male genital microenvironment on fertility, with the characterization female, male, and both intra- and inter- couple signatures that underlie decreased fertility. In this proposal we aim to determine the effect of the female genital microenvironment (inflammation and microbiome) on implantation success, the seminal microenvironment on semen quality and male factor infertility, and to characterize the inter-couple signatures between female and male partner microenvironment that underlie combined decreased fertility. These studies will identify host and microbial factors associated with infertility and help understand both intra-individual and inter-partner interactions that could contribute to fertility outcomes, which could identify novel therapeutic strategies or predictive models to increase clinical pregnancy rates.