independent educational grants from Abbott, bioMerieux Inc, Johnson & Johnson, InflaRx GmbH, Sobi and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep and RISCinCOVID (granted to the Hellenic Institute for the Study of Sepsis).

has received honoraria from AbbVie USA, Abbott CH, Brahms GmbH, InflaRx GmbH, MSD Greece, Sobi and XBiotech Inc. was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. was supported by Helmholtz Initiative and Networking Fund (1800167). was supported by an ERC starting Grant (948207) and a Radboud University Medical Centre Hypatia Grant (2018). This study was supported by a Horizon 2020 ImmunoSep grant (#847422). The other authors have declared that no conflict of interest exists. Netea is a scientific founder of Trained Therapeutix Discovery, and has received research grants from Trained Therapeutix Discovery, GSK, ViiV Healthcare and Ono Pharma. Giamarellos-Bourboulis has received honoraria from AbbVie USA, Abbott CH, Brahms GmbH, InflaRx GmbH, MSD Greece, Sobi and XBiotech Inc. In conclusion, our findings shed light on the heterogeneous immune landscape underlying sepsis, and provide opportunities for patient stratification for future therapeutic development. In separate cohorts, urosepsis was characterized by heterogeneous MALS and immunosuppression monocyte signatures, while MALS-specific monocyte clusters showed overlapping transcriptional signatures with severe COVID-19. Unsupervised clustering analysis revealed the existence of MALS-specific monocyte clusters, as well as one sepsis-specific monocyte cluster that was linked to disease severity. Pronounced differences were detected in the transcriptional signature of monocytes from sepsis patients, with clear distinction between MALS and immune paralysis patients. We used single-cell RNA sequencing to profile circulating leukocytes of healthy controls and sepsis patients classified as either hyperinflammatory (macrophage activation-like syndrome ), immune paralysis, or unclassified (when criteria for neither of these two immune subgroups were applicable). Different immune phenotypes characterize sepsis patients, including hyperinflammation and/or immunosuppression, but the biological mechanisms driving this heterogeneity remain largely unknown.

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