Enteric pathogens cause millions of cases of hospitalizations and deaths among children, especially in low-income countries, but effective vaccines are not available.

Memory B cells are essential for an effective vaccine: their ability to quickly give rise to antibody-producing cells upon re-exposure assure long-term protection of the host. However, the study of intestinal memory B cells has been difficult due to the chronic stimulation on the immune system driven by the diverse members of the intestinal microbiome. Cellular and molecular requirements for intestinal memory B cell generation and maintenance have not yet been elucidated.

We recently established a platform to generate and track memory B cell specific for commensal bacteria in vivo. In Aim 1 we propose to elucidate how commensal bacteria generate intestinal memory B cells at a single cell level. Understanding at high molecular resolution how the mucosal immune system gives rise to an efficient protection against bacteria present in the intestine will help shed a light on the mechanism behind the generation, or lack thereof, of memory B cells upon oral vaccination.

The intestinal immune system not only integrates signals from immune cells and commensal bacteria, but it also responds to absorbed dietary nutrients: we recently showed that oxidized forms of cholesterol control several aspects of the immune response. Intestinal memory B cells specifically express a receptor that recognizes cholesterol-derived lipids: in Aim 2 we will characterize how dietary cholesterol shapes intestinal memory B cell generation and maintenance.

The long-term goal of this work is to facilitate the development of strategy to reprogram intestinal memory B cells response against enteric pathogen by targeting intestinal microbiome and selected metabolic pathways.