Kristina Broliden

Purpose and aims: The primary objective is to identify the host molecular signatures underlying the inflammatory disorder vulvovaginal candidiasis (VVC) in the female reproductive tract. We aim to characterize the microbiome and investigate the influence of bacterial taxa on host responses. Additionally, we will explore the implications of these findings for HIV susceptibility.Methods: Clinical data, vaginal mucosal secretions, and tissue samples, will be collected from study participants with VVC, the recurrent form ´RVVC´, and from healthy controls in cross-sectional and longitudinal studies. We will utilize multi-omics analyses and an ex-vivo tissue explant model. Transcriptomics, proteomics, and metabolomics data will be correlated among study groups and with C. albicans abundance. Mixed model analysis will assess the impact of bacterial taxa on host responses. Tissue blocks will be exposed to combinations of C. albicans and L. iners isolates, followed by HIV infection. The project will span four years.Significance: This research investigates the defense mechanisms of the human vaginal mucosal barrier in VVC, the interaction between C.albicans and the vaginal microbiome, and its impact on HIV infection risk. Established HIV risk markers include epithelial damage, pro-inflammatory responses, and an increased number of mucosal HIV target cells. This comprehensive characterization aims to enhance our understanding of VVC and inform strategies to reduce HIV susceptibility.

Despite women comprising half of the global population, research on vaginal microbiome-host interactions remains critically underdeveloped. This project addresses this gap by capturing microbiome dynamics and its associations with cervical cancer treatment and recovery. Key bacterial genes and proteins involved in biofilm formation, anti-inflammatory properties, and antimicrobial activity will be identified. Molecular and cellular analyses will elucidate host immune responses, carcinogenic pathways, and cell cycle signaling influenced by microbial activity. Spatial RNA and protein profiling will reveal the organization of microbiome-host interactions across the genital tract, providing novel insights into localized mechanisms underlying health and disease. Additionally, vaginal Lactobacillus will be engineered to deliver cytokines, potentially enhancing current cervical cancer therapies. This project integrates metagenomics, culturomics, long-read genomic sequencing, bulk and spatial transcriptomics, bacterial and host proteomics, and innovative methodologies to investigate the functional mechanisms of the vaginal microbiome. By addressing bacterial, host, spatial, and dynamic dimensions, it aims to uncover previously unknown mechanisms driving microbiota-host interactions in women’s health. Insights could also extend to related conditions such as bacterial vaginosis and HPV infections, significantly advancing women’s health research and therapeutic innovation.

Purpose and Aim: This project aims to address critical gaps in understanding host susceptibility to sexually transmitted viral infections. Using HIV as a model of a sexually transmitted viral infection of pandemic concern, we will identify viral entry mechanisms at the genital mucosa during the initial days to weeks following primary infection. Project Plan: Vaginal tissue samples have been collected from clinical cohorts of women representing populations experiencing social inequalities, including female sex workers and young women from Sub-Saharan Africa. A multi-omics approach will be employed to analyze these samples, incorporating spatial transcriptomics, multiplex imaging analysis, and in situ hybridization. Mechanisms of HIV susceptibility will be identified by comparing women at high risk of infection due to an anaerobic polymicrobial cerivocvaginal microbiome with those having a Lactobacillus-dominated micorbiome. The cellular and molecular landscape of acute HIV infection will be assessed by co-staining for viral RNA/DNA and host mucosal markers.Significance: The findings will guide the development of novel prophylactic compounds to establish a protective genital mucosal barrier, significantly reducing the risk of viral transmission. Potential treatments may include immunomodulatory, live biotherapeutic, or hormone therapies to enhance mucosal barrier integrity, offering broad-spectrum efficacy against various viral infections of pandemic concern.