Abstract: Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated its expansion in sepsis across thousands of patients using public transcriptomic data. Here, we show that expression of the MS1 program is associated with sepsis severity and is up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of this cell state, we developed a model for inducing MS1 by treatment of healthy hematopoietic stem and progenitor cells (HSPCs) with blood plasma from patients with severe bacterial or SARS-CoV-2 infection. We demonstrate that blood plasma from sepsis or COVID-19 patients induces emergency myelopoiesis and expression of the MS1 program in both monocytes and neutrophils. Furthermore, we found that plasma IL-6, and to a lesser extent, IL-10, correlated with increased myeloid output and expression of the MS1 program, and validated the requirement for these cytokines to induce the MS1 program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this model system, we demonstrate that MS1 cells are broadly immunosuppressive and have decreased responsiveness to stimulation. Our study highlights the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections and introduces a genetically manipulable system for studying sepsis-associated myeloid dysregulation in humans.