SARS-CoV-2 pathogenesis

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 20(5), P. 270 - 284

Published: March 30, 2022

Language: Английский

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Human genetic and immunological determinants of critical COVID-19 pneumonia

Nature, Journal Year: 2022, Volume and Issue: 603(7902), P. 587 - 598

Published: Jan. 28, 2022

Language: Английский

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Innate immune and inflammatory responses to SARS-CoV-2: Implications for COVID-19

Cell Host & Microbe, Journal Year: 2021, Volume and Issue: 29(7), P. 1052 - 1062

Published: May 17, 2021

Language: Английский

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Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(13)

Published: May 18, 2021

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at cellular level not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression entry–related host molecules all nasal epithelial cells, we show that protein levels are relatively high and their localizations restricted to apical side multiciliated cells. In addition, provide evidence patients with COVID-19 massively detected replicated within We observed these findings during stage when infected ciliated cells were rapidly replaced by differentiating precursor Moreover, our revealed was versus oral squamous epithelium. These results imply targeting epithelium could be an ideal strategy prevent propagation.

Language: Английский

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SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery

Cell Reports, Journal Year: 2021, Volume and Issue: 35(5), P. 109055 - 109055

Published: April 15, 2021

Language: Английский

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Human distal lung maps and lineage hierarchies reveal a bipotent progenitor

Nature, Journal Year: 2022, Volume and Issue: 604(7904), P. 111 - 119

Published: March 30, 2022

Language: Английский

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An organoid‐derived bronchioalveolar model for SARS‐CoV‐2 infection of human alveolar type II‐like cells

The EMBO Journal, Journal Year: 2020, Volume and Issue: 40(5)

Published: Dec. 7, 2020

Article11 January 2021Open Access Transparent process An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells Mart M Lamers orcid.org/0000-0002-1431-4022 Viroscience Department, Erasmus University Medical Center, Rotterdam, The NetherlandsThese authors contributed equally to this work Search more papers by author Jelte van der Vaart orcid.org/0000-0002-4126-8420 Oncode Institute, Hubrecht Royal Netherlands Academy Arts and Sciences Utrecht, Kèvin Knoops Maastricht Multimodal Molecular Imaging University, Maastricht, Samra Riesebosch Tim I Breugem Anna Z Mykytyn Joep Beumer orcid.org/0000-0002-2055-4444 Debby Schipper Karel Bezstarosti Proteomics Charlotte D Koopman Single Cell Discoveries, Nathalie Groen Raimond B G Ravelli Hans Q Duimel Jeroen A Demmers Georges Verjans orcid.org/0000-0002-2465-2674 Marion P Koopmans Mauro J Muraro Peter Peters Clevers Corresponding Author [email protected] orcid.org/0000-0002-3077-5582 Bart L Haagmans orcid.org/0000-0001-6221-2015 Information Lamers1, Vaart2, Knoops3, Riesebosch1, Breugem1, Mykytyn1, Beumer2, Schipper1, Bezstarosti4, Koopman5, Groen5, Ravelli3, Duimel3, Demmers4, Verjans1, Koopmans1, Muraro5, Peters3, *,2 *,1 1Viroscience 2Oncode 3The 4Proteomics 5Single *Corresponding author. Tel: +31 30 2121800; E-mail: 10 7044004; EMBO Journal (2021)40:e105912https://doi.org/10.15252/embj.2020105912 See also: SL Leibel & X Sun (March 2021) PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19), which may result in distress (ARDS), multiorgan failure, death. epithelium is major target virus, but representative models study virus host interactions detail are currently lacking. Here, we describe 2D air–liquid interface culture system was characterized confocal electron microscopy single-cell mRNA expression analysis. In model, cells, also basal rare neuroendocrine grown from 3D self-renewing fetal lung bud tip organoids. These cultures were readily infected with mainly surfactant protein C-positive being targeted. Consequently, significant viral titers detected analysis revealed induction I/III interferon response program. Treatment these low dose lambda 1 reduced replication. Hence, represent an experimental can be applied drug screens. Synopsis vitro investigation physiology has remained difficult. establishment profiling tissue allows cellular tropism testing treatment strategies syndromes. Bronchioalveolar-like derived organoids give rise bronchioalveolar-like air-exposed apical side. cultures, type-2-like particularly permissive infection. induces type-I/III vitro. sensitive lamda treatment. Introduction severe spread globally within several months after initial outbreak Wuhan, China, December (Zhu et al, 2020). World Health Organization (WHO) declared pandemic on March 11, 2020. As November 1, 2020, > 46,000,000 patients confirmed 1,200,000 deaths (WHO, belongs Sarbecovirus subgenus (genus Betacoronavirus, family Coronaviridae), together SARS-CoV (Andersen 2020; Coronaviridae Study Group International Committee Taxonomy V, Lu influenza-like illness associated broad spectrum clinical syndromes, ranging mild upper airway symptoms life-threatening pneumonia (Chen Wang Wolfel Xu This fulfills radiographic histological criteria (ARDS). Classically, ARDS caused damage alveoli, specifically that critical oxygen transport alveoli blood, triggered through inflammatory pathogens or toxins (Ware Matthay, 2000; Thompson 2017; Ackermann Barton Menter Raptis early events lead failure as initiated following replication (tenOever, 2016). After entry, determined receptor availability, generates pathogen-associated molecular patterns, RNA structures, pattern recognition receptors (PRRs). PRR signaling subsequently leads transcription antiviral genes; varies between pulmonary cell types (preprint: Ravindra Therefore, outcome greatly influenced cell, largely presence CoV entry receptor. lungs, angiotensin-converting enzyme (ACE2), (Hoffmann Walls Wrapp Zhou 2020), expressed ciliated II (Jia 2005; Hikmet Qi Ciliated have been identified animal COVID-19 (Hou Rockx previous work, using bronchial (Lamers contrast notoriously difficult culture, thus limiting our understanding COVID-19, other infections. Currently, standardized methods use immortal lines primary (van den Bogaard 2009). Immortal lines, however, do not fully recapitulate complexity space epithelium. Primary partially capture remain incapable undergoing passaging quickly lose their vivo phenotype restricts availability donor material (Logan Desai, 2015; Zacharias 2018). Importantly, adult recently shown poorly infection, emphasizing urgent need develop susceptible Hui Some induced pluripotent stem cell-derived able show differentiation (Gotoh 2014; Dye Jacob Yamamoto de Carvalho 2019; Riet yet challenging. progenitor system, competence, tropism, compared differentiated small Results Replication competence Human epithelial (HAE) established at into mature types. It already used source (Zhou 2018; Sachs We first (Appendix Fig S1A–C) demonstrated infects cultured (ALI) (Fig 1). grew relatively high titration VeroE6 1A B) quantification S1D). Shedding occurred predominantly apically S1E F). previously large (bronchial) extensively targeted 1C). addition, noted CC10+ club 1D), no MUC5AC+ goblet 1E). Figure 1. A, B. Infectious observed titrations washes 2, 24, 48, 72 h MOI 0.01 (A) 0.1 (B) (red). dotted line indicates lower limit detection. Error bars SEM. N = 4. H p.i. hours post-infection. C–E. Immunofluorescent staining cultures. Nucleoprotein (NP) stains capsid (red), colocalized marker AcTUB (green; (C, D, E)) CC10 (blue; (D)). Phalloidin included stain actin (C)). Goblet MUC5AC (E)). Scale indicate 50 μm. Data information: Nuclei stained Hoechst TOPRO white (C-E). Download figure PowerPoint Establishment Another organoid developed Nikolic al (2017), virology. conditions support long-term self-renewal multipotent SOX2+SOX9+ differentiate both cells. (LBT) canalicular stage lungs 16–17 pcw (post-conception weeks). expansion medium, activates EGF, FGF, WNT signaling, inhibits BMP TGFβ, vast majority 2A), ATII-L subpopulation HTII-280 antibody exclusively ATII (Gonzalez 2010) 2B). Organoid maintained 14 passages without apparent change morphology, SOX2 SOX9 expression. Next, contains alveolar-like could accessed side experiments. plated Transwell inserts medium. Based recent literature, reasoned addition mesenchyme would provide cues survival toward fate (Barkauskas 2013; Rawlins, Leeman 2019). reaching confluency, least days ALI 2C). mesenchymal bottom compartment increased frequency HTII-280+ S2A B). ALI, consisted multilayered single-layered squamous areas single layer mostly thin contained expressing ATI markers HOPX 2D) HTI-56 2E), well 2F) LPCAT1 2G) (Dobbs 1999; Gonzalez 2010; Gonzales 2015). SFTPC+ present top 2H). TP63+ 2I). Canalicular different donors resulted similar EV1-EV5), whereas some variation proliferation 1EVI J). Using mass spectrometry washes, secreted proteins SFTPA1, SFTPA2, SFTPB, SFTPD S3). LBT confluent before (2D non-ALI) ALI) exposure air indicated decreased during EV2-EV5A B), while gradually EV2-EV5). general increase ATI- ATII-related genes intermediate levels non-ALI EV2F, Tables EV1 EV2). composition differential 3A, Table EV3). While like DNAH10 3A), FOXJ1, SNTN 3B), enriched ATI&II makers SFTPA1 3). Moreover, neuroendocrine, tuft, 3B). All together, data contain bronchiolar-like therefore (PNEC) imaging S6B). SCGB3A2 single- S6C). 2. Self-renewing I- A. medium co-expressing Sox2 (green) Sox9 (white) actin. + pneumocytes C. Schematic model. D–I. Differentiated co-culture donor-specific fibroblasts. interface, express (HOPX, green, (D); HTI-56, (E)), (HTII-280, (F); LPCAT1, (G); SFTPC (SPC), (H)), (TP63 (P63), (I)) containing one layer. Dotted barrier (blue (A, (D–I)). Click here expand figure. EV1. comparison A–J. D), SPC (E, F), (G, H), TP63 (I, J) weeks Transwell. (blue). EV2. Transcriptomic A–E. Line graphs indicating normalized read count (3D LBT), transwell non-ALI), ALI). n error stdev. Graphs depicting SOX2. D) SFTPA2 SFTPB. (E) HOPX. F. Heatmaps LBT). LBT, ALI. Colored Z-scores log2-transformed values. EV3. Comparison published datasets AT2 (small ALI), (alveolar dataset purified (purified AT2). Barplot percentage annotated cluster. Color represents identity. Combined current GSM2855485 presented. Indicated annotation based separate clustering. Published "Purified AT2". Violin plots visualizing AT2-like comprise (clusters 0 2). Purified GSM2855485. 4 3 EV4. Apical shedding Viral (B). C, D. (C) qRT–PCR (D) compartments. EV5. Transmission (A–F) (G–K) A–F. Pulmonary (ATII-L) found recognizable double-membranes vesicles (Dmv) particles (circles). Next lamellar bodies (Lb), lysosomal internal (circle). Extracellular intercellular ATI-L (E), albeit concentration. Dashed circles outside cell. remnants dead detached (F) showed apical-shed (in marked lines), free particles. G–K. (CC; (H)) (GC; (K)) visible cross section 8 differentiation. (I) (J) infections (K). inside 5 μm G), 2.5 (B, H, K), (F), 500 nm (D, I, J), 250 E). 3. up- downregulated (bronchioalveolar) airway). Color-coded presented gene. To further investigate diversity performed sequencing 4). cluster (94.3% cells), smaller (4.9% population PNECs (0.9% cells) 4A). ATII-like (46.0% clusters 2) 4B–D; SFTPC, LPCAT1; Appendix S4A), proliferating (6.4% 4) 4E), (6.5% 3) 4F–H; AGER, CAV1, HOPX; S4B). (cluster 5) KRT5 4I J; S4C). PNEC 7) CHGA 4K; S4D). whether bulk EV3A) (Figs 4L M, EV3B C) freshly isolated did form t-SNE map M), overlapped alveolar, 4M EV3B). set g

Language: Английский

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Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses — are we our own worst enemy?

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(1), P. 47 - 56

Published: Nov. 26, 2021

Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human — severe coronavirus (SARS-CoV), Middle East SARS-CoV-2 have illustrated the epidemic pandemic potential coronaviruses, better understanding their disease-causing mechanisms is urgently needed for rational design therapeutics. Analyses patients revealed marked dysregulation immune system in cases infection, there ample evidence that aberrant responses are typified by impaired induction interferons, exuberant inflammatory delayed adaptive responses. In addition, various viral proteins been shown impair interferon signalling induce inflammasome activation. This suggests disease associated with mediated both dysregulated host active interference. Here we discuss our current involved each these scenarios. this Perspective, Lok-Yin Roy Wong Stanley Perlman consider how 2 (SARS-CoV-2) related able drive immunopathology. They provide an overview coronavirus-derived molecules interfere key innate responses, including pathways complement, NF-κB activation, as well activation immunity.

Language: Английский

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Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells

Nature Cell Biology, Journal Year: 2021, Volume and Issue: 24(1), P. 10 - 23

Published: Dec. 30, 2021

Language: Английский

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Severe Acute Respiratory Syndrome Coronavirus 2–Induced Immune Activation and Death of Monocyte-Derived Human Macrophages and Dendritic Cells

The Journal of Infectious Diseases, Journal Year: 2020, Volume and Issue: 223(5), P. 785 - 795

Published: Dec. 2, 2020

Abstract Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected patients and experimentally infected animals indicate a critical role for augmented expression proinflammatory chemokines cytokines in disease. Here, we demonstrate that SARS-CoV-2 infection human monocyte-derived macrophages (MDMs) dendritic cells was abortive, but induced the production multiple antiviral (interferon-α, interferon-β, tumor necrosis factor, interleukins 1β, 6, 10) chemokine (CXCL10). Despite lack efficient replication MDMs, profound interferon-mediated cell death host cells. Macrophage activation were not enhanced by exposure to low levels convalescent plasma, suggesting antibody-dependent enhancement does contribute death. Together, these results potentially plays major disease 2019 pathogenesis, even absence productive infection.

Language: Английский

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