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A recent estimate suggests that one in five deaths globally are associated with sepsis[1][1]. To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity[2][2],[3][3] and our lack of insight into sepsis immunopathology[4][4]. These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis[5][5]–[8][6]. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data[9][7]. Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections. ### Competing Interest Statement The Broad Institute, Massachusetts General Hospital, and MIT may seek to commercialize aspects of this work, and related applications for intellectual property have been filed. In addition, P.C.B. is a consultant to and an equity holder in a company, 10X Genomics, whose products were used in this study. R.M.B. serves on Advisory Boards at Merck and Genentech. N.H. is a consultant for Related Sciences and an equity holder in BioNTech. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-8 [7]: #ref-9

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