Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19

Cytokines in plasma from sepsis or severe COVID-19 patients induce production of suppressive myeloid cells from hematopoietic progenitors in vitro.
Myeloid suppressive cells enter the arena Patients with bacterial sepsis or severe COVID-19 have increased numbers of suppressive myeloid cells in their blood. Reyes et al. now show that similar cells can be induced by treatment of healthy human bone marrow progenitor cells in culture with plasma from patients with bacterial sepsis or severe COVID-19. The differentiation of suppressive myeloid cells in this cell model depended on the cytokines IL-6 and IL-10, indicating a role for systemic factors in inducing myeloid dysregulation in patients with severe infections.
Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.