Systemic infection or inflammation can result in long-lasting changes in hematopoiesis by skewing the differentiation of hematopoietic stem progenitor cells (HSPCs) toward myeloid cell lineages. Such reprogramming of HSPC potential is driven by epigenetic changes that alter gene expression programs. In Cell, Cheong et al. examine how severe SARS-CoV-2 infection in humans affects epigenetic states in HSPCs and alterations in hematopoiesis over time. The authors performed transcriptomic and epigenetic profiling on blood samples obtained in 2020 from convalescent patients with COVID-19 who had been hospitalized either 2–4 months (early) or 4–12 (late) months earlier and compared those with samples from healthy individuals or other critically ill patients who did not have COVID-19. They identified notable differences in chromatin accessibility and transcriptional profiles in CD14+ monocytes, which were increased in the post-COVID-19 blood samples; importantly, epigenetic profiles of the CD14+ monocytes from patients with late COVID-19 differed from those of patients with early COVID-19, as well as from those of healthy controls. Similarly, epigenetic differences were found in CD34+ HSPCs from the samples from patients with early and late COVID-19, reflecting a durable change in hematopoietic cell potential and expression. Interestingly, given that their patient cohorts were recruited early in the pandemic, they were able to examine differential responses to tocilizumab (anti-IL-6R blockade), which some of the patients with late COVID-19 received during hospitalization. Treatment with anti-IL-6R reduced the myeloid cell skewing and partially rescued the epigenetic changes that were observed in the untreated patient HSPCs. Similar findings were observed for HSPCs in a mouse viral infection model in response to anti-IL-6R treatment. These findings show that durable epigenetic changes that affect gene expression are occurring in HSPCs and monocytes in patients with severe COVID-19, which may contribute to some of the post-acute sequelae observed in patients with long COVID.
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