Unraveling the molecular mechanisms of innate immune memory in humans

Innate immune cells have classically been considered to have no immunological memory. However, recent studies have challenged this dogma by demonstrating that innate immune cells, particularly monocytes and macrophages, can mount long-term memory and resistance to reinfection. These observations led to the concept of "trained immunity" - a phenomenon in which innate immune cells such as monocytes/macrophages and NK cells develop a faster and more robust immune response upon secondary stimulations by either the same or an unrelated pathogen. Epigenetic reprogramming is thought to be central to the induction of trained immunity. Yet, there is still a lack of comprehensive mechanistic knowledge of what are the specific epigenetic determinants required to induce long-lasting trained immunity in humans. Using combined expertise in functional genomics, computational biology, human immunology, and infectious diseases, this project will address three outstanding questions in the field: What is that nature of the epigenetic changes induced by "trained immunity adjuvants" in human myeloid and lymphoid progenitor cells? What trained immunity-induced epigenetic changes can be transmitted from the bone marrow hematopoietic stem cells to their differentiated counterpart cells in humans? What are the genetic and molecular determinants of inter-individual variation in trained immunity? In Aim 1, we will use single-cell gene expression and chromatin accessibility profiling (as an overall mark of epigenetic remodeling) to measure cell type-specific epigenetic and transcriptional signatures at the level of progenitor cells in the bone marrow of individuals that have been vaccinated with Bacille Calmette-Guerin (BCG) alone, beta-glucan (trained immunity adjuvant), BCG + beta-glucan, or placebo (control group). In Aim 2, we will ask how the transcriptional, and epigenetic changes induced by vaccination/adjuvants impact the function of cells from both the myeloid and lymphoid lineages. We will do so both in vitro (re-stimulation of peripheral blood mononuclear cells) and in vivo (secondary immune challenge with BCG). In Aim 3, we will use a response quantitative trait loci (QTL) mapping approach to identify genetic and epigenetic factors associated with inter-individual variation in trained immunity. This work will yield unique insight into the molecular mechanism necessary for the induction of long-lasting trained immunity in humans. In addition, it will provide a roadmap of the genetic and epigenetic factors underlying inter-individual variation in the induction of trained immunity, a critical step towards understanding the basis of population variation in response to vaccines and other immune stimuli.