A01 - Elucidation of the immune response and of the impact of the microbiome in murine calcific aortic valve stenosis

This project addresses inflammatory immune mechanisms and the role of the microbiome in the development of aortic valve stenosis (AS) using the consortium’s wire-induced AS model in mice and patient cohorts. We found that the intestinal microbiome is important for AS progression and propose identifying the pathogenic bacterial genera and defining circulating microbial-derived metabolites that impact AS development. We furthermore found a role for regulatory T cells and will identify pathogenic factors they produce and investigate whether their effect on AS may be mediated indirectly through microbiome alterations. We will also study the role of macrophage subsets and Galectin-3 as mediators in fibrotic tissue remodelling. Additionally, we will analyse the role of the profibrotic tissue factor Interleukin-22. We will translate our findings by examining in AS and control patients the pathogenic factors identified in the mouse model, i.e., pathogenic microbiome, circulating metabolites, Tregs, and specific macrophage subsets, which are involved in tissue remodelling. Our long-term goal is to identify novel pathogenic players as potential targets for future therapies in AS.