Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progen-itors--

Abstract

Abstract Through epigenetic mechanisms, systemic inflammation may trigger innate immune memory and persistent changes in hematopoietic cells; however, it has been difficult to investigate these phenotypes in the context of human disease, such as severe coronavirus disease 2019 (COVID-19). We developed a new workflow to isolate circulating hematopoietic stem and progenitor cells (HSPC) from peripheral blood, combining single-cell RNA/ATAC-seq. With this method, we were able to capture the diversity of circulating HSPC as seen in bone marrow, allowing for the non-invasive investigation of hematopoiesis as well as epigenomic changes after COVID-19. Following severe COVID-19, we observed both transcriptomic and epigenetic changes in HSPC and its progeny innate immune cells, and they persisted for months to a year. Different transcription factor activities (including IRF, AP-1, and CTCF) were associated with these alterations, which altered the regulation of inflammatory programs. Severe COVID-19 patients’ HSPC displayed long-lasting increases in myelopoiesis and granulopoiesis, and circulating monocytes responded more strongly to subsequent stimulation. We found that epigenomic changes in HSPC were retained and passed onto differentiated progeny innate immune cells. In addition, we demonstrate that administration of an anti-IL-6 blockade during acute severe COVID-19 can normalize the persistent phenotypes, suggesting that IL-6 plays a role in the development of epigenetic memory. In conclusion, epigenetic reprogramming of HSPC may underlie altered immune function subsequent to infection and has broad applicability, particularly for millions of COVID-19 survivors with incomplete recovery.