Long-term suppression of interferon programs and stress-associated transcriptional remodeling in human CD34+Lin−CD45+ hematopoietic progenitor cells following SARS-CoV-2 infection

Although SARS-CoV-2 primarily targets the respiratory system, increasing evidence indicates systemic effects that extend to the hematopoietic compartment. However, the long-term impact of infection on hematopoietic stem and progenitor cells (HSPCs) remains poorly defined. Here, we performed bulk RNA sequencing of highly purified peripheral blood CD34 + Lin − CD45 + hematopoietic progenitors obtained during active SARS-CoV-2 infection and at 3 and 9 months post-infection, as well as SARS CoV-2-negative controls. Bulk RNA sequencing of purified CD34 + Lin − CD45 + HSPCs revealed transcriptional remodeling characterized by coordinated suppression of type I interferon–regulated genes (IFIT1, OAS1, RSAD2, IFI44L, SIGLEC1, XAF1, UBA7 and CMPK2) detectable up to 3 months post-infection. In parallel, stress-associated transcriptional programs were upregulated, including regulators linked to stem cell plasticity and metabolic adaptation. Together, these findings suggest that SARS-CoV-2 infection is associated with long-lasting alterations in the transcriptional landscape of human CD34 + Lin − CD45 + hematopoietic progenitors cells circulating in the peripheral blood beyond the acute phase of disease. Rather than reverting fully to baseline quiescence, the progenitor compartment appears to adopt a rebalanced state marked by attenuated antiviral signaling and activation of stress-adaptive pathways. These results provide a stem cell–centric perspective on post-infectious immune adaptation and establish a framework for investigating long-term hematopoietic consequences of systemic viral infection.