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1.
Cell Rep Med ; 2(5): 100287, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1683718

ABSTRACT

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

2.
Nat Med ; 27(3): 546-559, 2021 03.
Article in English | MEDLINE | ID: covidwho-1319033

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/physiology , Sequence Analysis, RNA/statistics & numerical data , Single-Cell Analysis/statistics & numerical data , Virus Internalization , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Datasets as Topic/statistics & numerical data , Demography , Female , Gene Expression Profiling/statistics & numerical data , Humans , Lung/metabolism , Lung/virology , Male , Middle Aged , Organ Specificity/genetics , Respiratory System/metabolism , Respiratory System/virology , Sequence Analysis, RNA/methods , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis/methods
3.
Cell Rep Med ; 2(5): 100287, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1213572

ABSTRACT

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

4.
Nat Med ; 27(3): 546-559, 2021 03.
Article in English | MEDLINE | ID: covidwho-1114717

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.


Subject(s)
COVID-19/epidemiology , COVID-19/genetics , Host-Pathogen Interactions/genetics , SARS-CoV-2/physiology , Sequence Analysis, RNA/statistics & numerical data , Single-Cell Analysis/statistics & numerical data , Virus Internalization , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Datasets as Topic/statistics & numerical data , Demography , Female , Gene Expression Profiling/statistics & numerical data , Humans , Lung/metabolism , Lung/virology , Male , Middle Aged , Organ Specificity/genetics , Respiratory System/metabolism , Respiratory System/virology , Sequence Analysis, RNA/methods , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis/methods
5.
Cell ; 181(5): 1016-1035.e19, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-100497

ABSTRACT

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.


Subject(s)
Alveolar Epithelial Cells/metabolism , Enterocytes/metabolism , Goblet Cells/metabolism , Interferon Type I/metabolism , Nasal Mucosa/cytology , Peptidyl-Dipeptidase A/genetics , Adolescent , Alveolar Epithelial Cells/immunology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/physiology , COVID-19 , Cell Line , Cells, Cultured , Child , Coronavirus Infections/virology , Enterocytes/immunology , Goblet Cells/immunology , HIV Infections/immunology , Humans , Influenza, Human/immunology , Interferon Type I/immunology , Lung/cytology , Lung/pathology , Macaca mulatta , Mice , Mycobacterium tuberculosis , Nasal Mucosa/immunology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Receptors, Virus/genetics , SARS-CoV-2 , Serine Endopeptidases/metabolism , Single-Cell Analysis , Tuberculosis/immunology , Up-Regulation
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