Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19

Bernardes, Joana P.; Mishra, Neha; Tran, Florian; Bahmer, Thomas; Best, Lena; Blase, Johanna I.; Bordoni, Dora; Franzenburg, Jeanette; Geisen, Ulf; Josephs‐Spaulding, Jonathan; Köhler, Philipp; Künstner, Axel; Rosati, Elisa; Aschenbrenner, Anna C.; Bächer, Petra; Baran, Nathan; Boysen, Teide Jens; Brandt, Burkhard; Bruse, Niklas; Dörr, Jonathan; Dräger, Andreas; Elke, Gunnar; Ellinghaus, David; Fischer, Julia; Förster, Michael; Franke, André; Franzenburg, Sören; Frey, Norbert; Friedrichs, Anette; Fuß, Janina; Glück, Andreas; Hamm, Jacob; Hinrichsen, Finn; Hoeppner, Marc P.; Imm, Simon; Junker, Ralf; Kaiser, Sina; Kan, Ying H.; Knoll, Rainer; Lange, Christoph; Laue, Georg; Lier, Clemens; Lindner, Matthias; Μαρίνος, Γεώργιος; Markewitz, Robert; Nattermann, Jacob; Noth, Rainer; Pickkers, Peter; Rabe, Klaus F.; Renz, Alina; Röcken, Christoph; Rupp, Jan; Schaffarzyk, Annika; Scheffold, Alexander; Schulte-Schrepping, Jonas; Schunk, Domagoj; Skowasch, Dirk; Ulas, Thomas; Wandinger, Klaus‐Peter; Wittig, Michael; Zimmermann, Johannes; Busch, Hauke; Hoyer, Bimba F.; Kaleta, Christoph; Heyckendorf, Jan; Kox, Matthijs; Rybniker, Jan; Schreiber, Stefan; Rosenstiel, Philip; Banovich, Nicholas E.; Desai, Tushar J.; Eickelberg, Oliver; Haniffa, Muzlifa; Horváth, Péter; Kropski, Jonathan A.; Lafyatis, Robert; Lundeberg, Joakim; Meyer, Kerstin B.; Nawijn, Martijn C.; Nikolić, Marko; Montañes, José Ordovas; Pe’er, Dana; Tata, Purushothama Rao; Rawlins, Emma L.; Regev, Aviv; Reyfman, Paul A.; Samakovlis, Christos; Schultze, Joachim L.; Shalek, Alex K.; Shepherd, Douglas P.; Spence, Jason R.; Teichmann, Sarah A.; Theis, Fabian J.; Tsankov, Alexander M.; Berge, Maarten van den; Papen, Michael von; Whitsett, Jeffrey A.; Zaragosi, Laure‐Emmanuelle; Angelov, Angel; Bals, Robert; Bartholomäus, Alexander; Becker, Anke; Bezdan, Daniela; Bonifacio, Ezio E.; Bork, Peer; Clavel, Thomas; Colme-Tatche, 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; Landthaler, Markus; Li, Yang; 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; Saliba, Antoine‐Emmanuel; Sander, Leif Erik; Sawitzki, Birgit; Schiffer, Philipp H.; Schulte, Eva-Christina; Sczyrba, Alexander; Stegle, Oliver; Stoye, Jens; Vehreschild, Janne; Vogel, Jörg; Kleist, Max von; Walker, Andreas; Walter, Jörn; Wieczorek, Dagmar; Ziebuhr, John

doi:10.1016/j.immuni.2020.11.017

Cited by 314 publications

(387 citation statements)

References 103 publications

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“…In line with those results, we observed attenuated IFN response in the CSF of severe Neuro-COVID and compared with viral encephalitis. Inversely, many studies reported an expansion of plasma cells and plasmablasts ( Bernardes et al., 2020 ; Zhang et al., 2020 ; Zhu et al., 2020 ) that we did not observe in the CSF. Immune alterations may thus be partially shared between compartments and partially compartment specific.…”

Section: Discussioncontrasting

confidence: 80%

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

et al. 2021

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Section: Discussioncontrasting

confidence: 80%

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

et al. 2021

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“…How heme and OXPHOS transcriptional programmes are linked on a molecular level cannot be inferred from our data. Erythroid cell activation has recently been detected in severe COVID-19 (Bernardes et al, 2020) and could also contributes to a heme transcriptional signature. However, the increase in heme metabolism in our cohort correlates strongly with a falling haemoglobin, and reticulocytes ( Figure S7 ) in patients in groups C, D and E are low – suggesting suppression rather than activation of erythropoiesis in these individuals.…”

Section: Discussionmentioning

confidence: 99%

Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

Bergamaschi

Mescia

Turner

et al. 2021

Preprint

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SummaryIn a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.

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“…T cell lymphopenia is a hallmark of acute viral infection, including severe COVID-19 (52) (24) (53) (54), especially within the CD8 T cell compartment (50, 51, 54) and with advanced age (52). This is often accompanied by a concomitant accumulation of memory T cells, particularly in EM and TEMRA subsets (53) (50) (25).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity

Lewis

Sureshchandra

Zulu

et al. 2021

Preprint

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Severe COVID-19 disproportionately impacts older individuals and those with comorbidities. It is estimated that approximately 80% of COVID-19 deaths are observed among individuals >65 years of age. However, the immunological underpinnings of severe COVID-19 in the aged have yet to be defined. This study captures the longitudinal immune response to SARS-CoV-2 infection in a cohort of young and aged patients with varying disease severity. Phenotypic transcriptional and functional examination of the peripheral mononuclear cells revealed age-, time, and disease severity-specific adaptations. Gene expression signatures within memory B cells suggest qualitative differences in the antibody responses in aged patients with severe disease. Examination of T cells showed profound lymphopenia, that worsened over time and correlated with lower levels of plasma cytokines important for T cell survival in aged patients with severe disease. Single cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity, and type-I interferon signaling in memory T cells and NK cells. Although hallmarks of a cytokine storm were evident in both groups, older individuals exhibited elevated levels of chemokines that mobilize inflammatory myeloid cells, notably in those who succumbed to disease. Correspondingly, we observed a re-distribution of DC and monocytes with severe disease that was accompanied by a rewiring towards a more regulatory phenotype. Several of these critical changes, such as the reduction of surface HLA-DR on myeloid cells, were reversed in young but not aged patients over time. In summary, the data presented here provide novel insights into the impact of aging on the host response to SARS-CoV2 infection.

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Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19

Cited by 314 publications

References 103 publications

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid

Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity

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