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

Abstract

A recent estimate suggests that one in five deaths globally are associated with sepsis1. To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity2,3 and our lack of insight into sepsis immunopathology4. These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis5–8. 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 data9. 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.

Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity

“…Several factors are involved in the expansion of M-MDSCs, including IL-6 and GM-CSF (14). Furthermore, IL-6 and IL-10 have been shown to be essential in inducing emergency myelopoiesis resulting in expansion of an M-MDSC-like cell subset in severe COVID-19 (47). In line with previous studies (12,33), we demonstrated a relationship between IL-6 and COVID-19 disease severity.…”

Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions

“…36,38,55 Many severity-associated proteins were also associated with the nuclear factor kB (NF-kB) pathway, showing substantial overlap with published bronchial and nasopharyngeal cells collected from patients, 38,55 genes induced by TNF-a in monocytes in vitro, 56 and a TNF-a pathway signature observed by scRNA-seq in COVID-19 severity-associated monocytes. 17,57 Few severity-associated proteins were part of the type I IFN response, in agreement with published data 4,7 and with the association of COVID-19 severity with genetic variants that weaken IFN-related viral sensing. 58 Our proteomic analysis of a large cohort of COVID-19 patients reveals COVID-19 severity-and mortality-associated pathways that may serve as potential therapeutic targets and provide the basis for diagnostics to stratify highrisk patients for tailored therapies and earlier interventions.…”

Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection

“…This suggests that besides the early increase in CD169 + monocytes in all COVID-19 patients associated with T cell dysfunctions, the immunological response to SARS-CoV-2 infection features multiple alterations of monocytic subsets reflecting the severity of the disease. Consistent with these data, it was shown that CD14 + HLA-DR low cells were increased in critical COVID-19 patients, 21,26,[56][57][58] while CD14 low CD16 + monocytes, able to migrate to the lung, were correlated with the length of stay in the ICU. 15,23,59 Our study correlates the accumulation of nonclassical monocytes and M-MDSCs occurring during the first days of ICU to adverse events.…”