Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Schulte-Schrepping, Jonas; Reusch, Nico; Paclik, Daniela; Baßler, Kevin; Schlickeiser, Stephan; Zhang, Bowen; Krämer, Benjamin; Krammer, Tobias; Brumhard, Sophia; Bonaguro, Lorenzo; Domenico, Elena De; Wendisch, Daniel; Grasshoff, Martin; Kapellos, Theodore S.; Beckstette, Michael; Pecht, Tal; Saglam, Adem; Dietrich, Oliver; Mei, Henrik E.; Schulz, Axel; Conrad, C.; Kunkel, Désirée; Vafadarnejad, Ehsan; Xu, Cheng‐Jian; Horne, Arik; Herbert, Miriam; Drews, Anna; Thibeault, Charlotte; Pfeiffer, Moritz; Hippenstiel, Stefan; Hocke, Andreas C.; Müller-Redetzky, Holger; Heim, Katrin Moira; Machleidt, Felix; Uhrig, Alexander; Jarcy, Laure Bosquillon de; Jürgens, Linda; Stegemann, Miriam; Glösenkamp, Christoph R.; Volk, Hans‐Dieter; Goffinet, Christine; Landthaler, Markus; Wyler, Emanuel; Georg, Philipp; Schneider, Maria; Dang-Heine, Chantip; Neuwinger, Nick; Kappert, Kai; Tauber, Rudolf; Corman, Victor M.; Raabe, Jan; Kaiser, Kim M; Vinh, Michael To; Rieke, Gereon J; Meisel, Christian; Ulas, Thomas; Becker, Matthias; Geffers, Robert; Witzenrath, Martin; Drosten, Christian; Suttorp, Norbert; Kalle, Christof von; Kurth, Florian; Händler, Kristian; Schultze, Joachim L.; Aschenbrenner, Anna C.; Li, Yang; Nattermann, Jacob; Sawitzki, Birgit; Saliba, Antoine‐Emmanuel; Sander, Leif Erik; Angelov, Angel; Bals, Robert; Bartholomäus, Alexander; Becker, Anke; Bezdan, Daniela; Bonifacio, Ezio E.; Bork, Peer; Clavel, Thomas; Colomé-Tatché, Maria; Diefenbach, Andreas; Dilthey, Alexander; Fischer, Nicole; Förstner, Konrad U.; Frick, Julia-Stefanie; Gagneur, Julien; Goesmann, Alexander; Hain, Torsten; Hummel, Michael; Janssen, Stefan; Kalinowski, Jörn; Kallies, René; Kehr, Birte; Keller, Andreas; Kim-Hellmuth, Sarah; Klein, Christoph; Kohlbacher, Oliver; Korbel, Jan O.; Kurth, Ingo; Ludwig, Kerstin U.; Makarewicz, Oliwia; Marz, Manja; McHardy, Alice C.; Mertes, Christian; Nöthen, Markus M.; Nürnberg, Peter; Ohler, Uwe; Ossowski, Stephan; Overmann, Jörg; Peter, Silke; Pfeffer, Klaus; Poetsch, Anna R.; Pühler, Alfred; Rajewsky, Nikolaus; Ralser, Markus; Rieß, Olaf; Ripke, Stephan; Rocha, Ulisses Nunes da; Rosenstiel, Philip; Schiffer, Philipp H.; Schulte, Eva-Christina; Sczyrba, Alexander; Stegle, Oliver; Stoye, Jens; Theis, Fabian J.; Vehreschild, Janne; Vogel, Jörg; Kleist, Max von; Walker, Andreas; Walter, Jörn; Wieczorek, Dagmar; Ziebuhr, John

doi:10.1016/j.cell.2020.08.001

Cited by 1,295 publications

(1,804 citation statements)

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“…Previous studies have reported opposing effects of MDSCs on sepsis outcomes [24][25][26][27] , warranting further investigation into their function and association with patient prognosis. Signatures similar to MS1 have also been described recently in severe SARS-CoV-2 infections 28,29 , but have not been systematically analyzed across multiple cohorts. Here, we identify the gene expression programs associated with the MS1 cell state and determine their relationship with disease severity in both bacterial sepsis and COVID-19.…”

Section: Main Textmentioning

confidence: 99%

“…To determine whether MS1 cells are similarly expanded in severe COVID-19, we analyzed four COVID-19 scRNA-seq datasets 7,28,34,35 independently and identified gene expression modules in CD14+ monocytes from each dataset using an unbiased cNMF method ( Figure 1a, Supplementary Figure 2 ). In each of the four studies, we found gene expression modules corresponding to the MS1 and MHC-II modules, as evidenced by their strong correlation (Pearson r > 0.8) with modules from our sepsis data ( Figure 1d ).…”

Section: Main Textmentioning

confidence: 99%

“…Boxes show the median and IQR for each patient cohort, with whiskers extending to 1.5 IQR in either direction from the top or bottom quartile. Detailed description of the patient cohorts and number of cells and patients for each dataset in (d,e) are outlined in the corresponding publications7,9,28,34,35 . Control, healthy controls; Leuk-UTI, urinary tract infection with leukocytosis; Int-URO, intermediate urosepsis; URO, urosepsis; Bac-SEP, sepsis with confirmed bacteremia; ICU-SEP, intensive care with sepsis; ICU-NoSEP, intensive care without sepsis; M-COV, mild COVID-19; S-COV, severe COVID-19; S-FLU, severe influenza A.…”

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confidence: 99%

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

Reyes

Filbin

Bhattacharyya

et al. 2020

Preprint

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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.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

mentioning

confidence: 99%

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

Reyes

Filbin

Bhattacharyya

et al. 2020

Preprint

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“…In addition, elevated levels of interleukin (IL)-6 and IL-8, well-known inducers of MDSCs 11-13 , are observed in severe cases of COVID-19 14,15 . This information suggests a possible link between MDSCs and COVID-19. The expansion of MDSCs and MDSC-like cells has been repeatedly observed in severe COVID-19 patients by several research groups from different countries [16][17][18][19][20][21][22] . However, to gain insight into the roles of MDSCs in COVID- 19, it is important to analyze the cell subsets in association with different clinical outcomes (e.g.…”

Section: Introductionmentioning

confidence: 84%

Myeloid cell dynamics correlate with clinical outcomes of severe coronavirus disease 2019

Takano

Matsumoto

Adachi

et al. 2020

Preprint

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An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19); however, it remains unclear whether myeloid cells are beneficial or detrimental to the clinical outcome. Here, we tracked cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis by flow cytometric analysis of blood samples from COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, rather than other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Notably, this subset was selectively expanded in survivors of severe cases and diminished during recovery. Analysis of plasma cytokines/chemokines revealed that interleukin-8 increased prior to PMN-MDSC expansion in survivors and returned to basal levels during the recovery phase. In contrast, interleukin-6 and interferon--induced protein 10 were abundantly induced in non-survivors, suggesting possible downstream targets for the immunosuppressive effects of the MDSC subset. Our data indicate that increased cellularity of PMN-MDSCs might be beneficial for the clinical outcome and could be useful as a possible predictor of prognosis in cases of severe COVID-19.

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“…Peripheral blood mononuclear cell (PBMC) studies have demonstrated dysregulated myeloid (monocyte and neutrophil) and CD8 + T cell compartments in severe COIVD-19 (3,8,9). Currently, there are only a few studies focusing on lung local responses.…”

Section: Mainmentioning

confidence: 99%

Dysregulation of Pulmonary Responses in Severe COVID-19

Yang

2020

Preprint

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Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17 type cells, decreased IFNA1 expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), Hyaluronan synthase 2 (HAS2), and Plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID19.

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Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

Cited by 1,295 publications

References 140 publications

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

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

Myeloid cell dynamics correlate with clinical outcomes of severe coronavirus disease 2019

Dysregulation of Pulmonary Responses in Severe COVID-19

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