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1.
Cell death and differentiation ; : 1-3, 2022.
Article in English | EuropePMC | ID: covidwho-1749132
2.
Cells ; 11(5)2022 03 01.
Article in English | MEDLINE | ID: covidwho-1715131

ABSTRACT

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.


Subject(s)
COVID-19 , Lymphohistiocytosis, Hemophagocytic , Artificial Intelligence , COVID-19/complications , COVID-19/genetics , Child , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Neutrophil Activation , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
3.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1536467

ABSTRACT

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.


Subject(s)
COVID-19/pathology , COVID-19/virology , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Macrophages/pathology , Macrophages/virology , SARS-CoV-2/physiology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , COVID-19/diagnostic imaging , Cell Communication , Cohort Studies , Fibroblasts/pathology , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/diagnostic imaging , Idiopathic Pulmonary Fibrosis/genetics , Mesenchymal Stem Cells/pathology , Phenotype , Proteome/metabolism , Receptors, Cell Surface/metabolism , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Tomography, X-Ray Computed , Transcription, Genetic
4.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1442406

ABSTRACT

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Base Sequence , Humans , Immunity, Innate/immunology , Inflammation/immunology , Interferon-alpha/blood , Pulmonary Fibrosis/pathology , RNA-Seq , Severity of Illness Index , Transcriptome/genetics , United Kingdom , United States
5.
Front Immunol ; 12: 720109, 2021.
Article in English | MEDLINE | ID: covidwho-1348492

ABSTRACT

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease's pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.


Subject(s)
COVID-19/immunology , HLA-DR Antigens/immunology , Macrophages/immunology , Monocytes/immunology , SARS-CoV-2/immunology , COVID-19/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Macrophages/pathology , Monocytes/pathology , Severity of Illness Index
6.
Biospektrum (Heidelb) ; 27(3): 227, 2021.
Article in German | MEDLINE | ID: covidwho-1225064
7.
Front Immunol ; 12: 652470, 2021.
Article in English | MEDLINE | ID: covidwho-1204206

ABSTRACT

Strong evidence has been accumulated since the beginning of the COVID-19 pandemic that neutrophils play an important role in the pathophysiology, particularly in those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention to neutrophils has uncovered their fascinating transcriptional and functional diversity as well as their developmental trajectories. These new findings are important to better understand the many facets of neutrophil involvement not only in COVID-19 but also many other acute or chronic inflammatory diseases, both communicable and non-communicable. Here, we highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophils and their reactivity in patients with COVID-19.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , Neutrophils/immunology , Pandemics , SARS-CoV-2/immunology , Humans
8.
Front Immunol ; 12: 652470, 2021.
Article in English | MEDLINE | ID: covidwho-1177980

ABSTRACT

Strong evidence has been accumulated since the beginning of the COVID-19 pandemic that neutrophils play an important role in the pathophysiology, particularly in those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention to neutrophils has uncovered their fascinating transcriptional and functional diversity as well as their developmental trajectories. These new findings are important to better understand the many facets of neutrophil involvement not only in COVID-19 but also many other acute or chronic inflammatory diseases, both communicable and non-communicable. Here, we highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophils and their reactivity in patients with COVID-19.


Subject(s)
COVID-19/epidemiology , COVID-19/immunology , Neutrophils/immunology , Pandemics , SARS-CoV-2/immunology , Humans
9.
Cell ; 184(7): 1671-1692, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1085578

ABSTRACT

The introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the human population represents a tremendous medical and economic crisis. Innate immunity-as the first line of defense of our immune system-plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for coronavirus disease 2019 (COVID-19), the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which so far are lagging behind.


Subject(s)
COVID-19/immunology , Host Microbial Interactions , Immunity, Innate , SARS-CoV-2/physiology , Humans , Severity of Illness Index
10.
Genome Med ; 13(1): 7, 2021 01 13.
Article in English | MEDLINE | ID: covidwho-1027902

ABSTRACT

BACKGROUND: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. METHODS: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. RESULTS: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. CONCLUSIONS: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.


Subject(s)
COVID-19/pathology , Neutrophils/metabolism , Transcriptome , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Case-Control Studies , Down-Regulation , Drug Repositioning , Humans , Neutrophils/cytology , Neutrophils/immunology , Phenotype , Principal Component Analysis , RNA/blood , RNA/chemistry , RNA/metabolism , Sequence Analysis, RNA , Severity of Illness Index , Up-Regulation
11.
STAR Protoc ; 1(3): 100233, 2020 12 18.
Article in English | MEDLINE | ID: covidwho-978460

ABSTRACT

In December 2019, a new coronavirus, SARS-CoV-2, which causes the respiratory illness that led to the COVID-19 pandemic, was reported. In the face of such a new pathogen, special precautions must be taken to examine potentially infectious materials due to the lack of knowledge on disease transmissibility, infectivity, and molecular pathogenicity. Here, we present a complete and safe workflow for performing scRNA-seq experiments on blood samples of infected patients from cell isolation to data analysis using the micro-well based BD Rhapsody platform. For complete information on the use and execution of this protocol, please refer to Schulte-Schrepping et al. (2020).


Subject(s)
COVID-19 , Communicable Diseases , RNA-Seq/methods , Single-Cell Analysis/methods , Transcriptome/genetics , Biomarkers/blood , COVID-19/genetics , COVID-19/metabolism , Communicable Diseases/genetics , Communicable Diseases/metabolism , Humans , SARS-CoV-2 , Workflow
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