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Immunity ; 54(4): 753-768.e5, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1385739


Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.

Immunity/genetics , Virus Diseases/immunology , Antigen Presentation/genetics , Cohort Studies , Hematopoiesis/genetics , Humans , Interferons/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Myeloid Cells/immunology , Myeloid Cells/pathology , Prognosis , Severity of Illness Index , Systems Biology , Transcriptome , Virus Diseases/blood , Virus Diseases/classification , Virus Diseases/genetics , Viruses/classification , Viruses/pathogenicity
Front Immunol ; 12: 651656, 2021.
Article in English | MEDLINE | ID: covidwho-1211812


Although immune dysfunction is a key feature of coronavirus disease 2019 (COVID-19), the metabolism-related mechanisms remain elusive. Here, by reanalyzing single-cell RNA sequencing data, we delineated metabolic remodeling in peripheral blood mononuclear cells (PBMCs) to elucidate the metabolic mechanisms that may lead to the progression of severe COVID-19. After scoring the metabolism-related biological processes and signaling pathways, we found that mono-CD14+ cells expressed higher levels of glycolysis-related genes (PKM, LDHA and PKM) and PPP-related genes (PGD and TKT) in severe patients than in mild patients. These genes may contribute to the hyperinflammation in mono-CD14+ cells of patients with severe COVID-19. The mono-CD16+ cell population in COVID-19 patients showed reduced transcription levels of genes related to lysine degradation (NSD1, KMT2E, and SETD2) and elevated transcription levels of genes involved in OXPHOS (ATP6V1B2, ATP5A1, ATP5E, and ATP5B), which may inhibit M2-like polarization. Plasma cells also expressed higher levels of the OXPHOS gene ATP13A3 in COVID-19 patients, which was positively associated with antibody secretion and survival of PCs. Moreover, enhanced glycolysis or OXPHOS was positively associated with the differentiation of memory B cells into plasmablasts or plasma cells. This study comprehensively investigated the metabolic features of peripheral immune cells and revealed that metabolic changes exacerbated inflammation in monocytes and promoted antibody secretion and cell survival in PCs in COVID-19 patients, especially those with severe disease.

COVID-19/immunology , Glycolysis/genetics , Lysine/metabolism , Monocytes/metabolism , Single-Cell Analysis/methods , Adenosine Triphosphatases/blood , Adenosine Triphosphatases/genetics , Antibodies/metabolism , COVID-19/metabolism , COVID-19/physiopathology , Databases, Genetic , GPI-Linked Proteins/metabolism , Gene Ontology , Hematopoiesis/genetics , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Lipopolysaccharide Receptors/metabolism , Lysine/genetics , Membrane Transport Proteins/blood , Membrane Transport Proteins/genetics , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/physiology , Monocytes/immunology , Monocytes/pathology , Oxidative Phosphorylation , RNA-Seq , Receptors, IgG/metabolism , Signal Transduction/genetics , Signal Transduction/immunology , Transcriptome/genetics