Shaping of long term innate immunity by viral education of bone marrow monocytes

ended

Symbiotic and pathogenic microbes are major environmental factors that play fundamental roles in shaping host immunity. Such dynamic interactions between commensals or pathogens and the host must be finely regulated to balance protective immune responses and induction of regulatory pathways. While frequently underestimated, immune imprinting by viruses is a key determinant for variation in disease susceptibility. Numerous evidence shows that a history of infections trains the innate immune system for the long term. Amongst the cells that are trained, monocytes are highly heterogeneous and are involved in essential biological processes such as anti-microbial activity, immunomodulation or macrophage-niche replenishment. While the current paradigm states that monocyte fate and function are driven by the local microenvironment, a recent study has shown that monocytes are primed in the bone marrow for functional properties. Here, we want to explore how and where monocyte development and function are educated by symbiotic (Murid herpesvirus 4) or pathogenic (Pneumonia Virus of Mice) viruses and with which potential outcomes for long-term immunity. To this end, we have devised three main aims. First, following infections, we will characterize monocytes and their progenitors by classical immunophenotyping, functional assays and unbiased single-cell RNA-seq in combination with ATAC-seq, to investigate in-depth how and where viruses shape monocytes and monocyte-derived cells. Second, molecular mechanism(s) underlying monocyte priming after infections will be assessed. In particular, based on literature and preliminary results, we postulate that bone marrow CD169+ macrophages could play a key role in early monocyte priming. Third, the consequences of virus-driven monocyte training will be investigated at steady state and upon heterologous challenges. Such research could provide the proof of concept that viral education of bone marrow monocytes shapes long-term innate immunity.