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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Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV

Nature, Journal Year: 2021, Volume and Issue: 594(7862), P. 246 - 252

Published: April 12, 2021

Language: Английский

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Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(6), P. 890 - 904.e8

Published: Oct. 21, 2020

Language: Английский

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Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(21)

Published: May 6, 2021

Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some these do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed integrated into DNA human cells culture transcription sequences might account for positive PCR seen patients. In support this hypothesis, we found copies genome infected cells. target site duplications flanking viral consensus LINE1 endonuclease recognition at integration sites, consistent with a retrotransposon-mediated, target-primed reverse retroposition mechanism. also found, patient-derived tissues, evidence suggesting large fraction is transcribed sequences, generating viral-host chimeric transcripts. The may thus contribute by infection clinical recovery. Because detected only subgenomic derived mainly 3' end host cell, virus cannot produced sequences.

Language: Английский

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Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis

Clinical Microbiology Reviews, Journal Year: 2021, Volume and Issue: 34(3)

Published: May 11, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and mortality rate of about 2.2%, as 10 December 2020. About 20% COVID-19 patients exhibit moderate to severe symptoms. manifests distress (ARDS) elevated plasma proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), (C-C motif) (CCL2), low levels interferon type I (IFN-I) in the early stage IFN-I during advanced COVID-19. Most critically ill have had preexisting comorbidities, hypertension, diabetes, cardiovascular diseases, diseases. These conditions are known perturb chemokines, angiotensin-converting enzyme (ACE2), an essential receptor involved SARS-CoV-2 entry into host cells. ACE2 downregulation infection activates angiotensin II/angiotensin (AT1R)-mediated hypercytokinemia hyperinflammatory syndrome. However, several proteins, open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, nucleocapsid (N) protein, can inhibit IFN II (IFN-I -II) production. Thus, hyperinflammation, combination lack responses against on infection, makes succumb Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling therapy would favor prognosis This review describes critical viral factors underpinning "cytokine storm" induction antagonism pathogenesis. Therapeutic reduce hyperinflammation their limitations also discussed.

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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Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2

Cell stem cell, Journal Year: 2020, Volume and Issue: 27(6), P. 905 - 919.e10

Published: Oct. 21, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type (hAT2) cells. Characterizing pathogenesis crucial for developing vaccines and therapeutics. However, lack models mirroring cellular physiology pathology hAT2 cells limits study. Here, we develop feeder-free, long-term, three-dimensional (3D) culture technique derived from primary tissue investigate infection response to SARS-CoV-2. By imaging-based analysis single-cell transcriptome profiling, reveal rapid viral replication increased expression interferon-associated genes proinflammatory in infected cells, indicating robust endogenous innate immune response. Further tracing mutations acquired during transmission identifies full individual effectively single entry. Our study provides deep insights into SARS-CoV-2 application defined 3D cultures as diseases.

Language: Английский

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NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 10, 2020

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, death. Data patients severe compared symptoms indicate that highly dysregulated exuberant inflammatory responses correlate severity disease lethality. Epithelial-immune cell interactions elevated cytokine chemokine levels, i.e. storm, seem play central role in lethality COVID-19. The present perspective places cellular pro-inflammatory signal pathway, NF-κB, the context recently published data for COVID-19 provides hypothesis therapeutic approach aiming at simultaneous inhibition whole cascades cytokines chemokines. cytokines/chemokines is expected have much higher potential as single target approaches prevent cascade (i.e. redundant, triggering, amplifying, synergistic) effects induced chemokines critical stage patients.

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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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection

Clinical Microbiology Reviews, Journal Year: 2021, Volume and Issue: 34(2)

Published: Jan. 12, 2021

To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants emerged in the 21st century. The newest member this group, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected at end 2019 Hubei province, China. Since then, novel has spread worldwide, causing a pandemic; disease caused by virus is called (COVID-19). clinical presentation ranges from asymptomatic mild tract infections and influenza-like illness with accompanying lung injury, multiorgan failure, death. Although lungs are believed be site which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting involvement gastrointestinal tract, heart, cardiovascular system, kidneys, organs; therefore, following question arises: COVID-19 or systemic disease? This review aims summarize existing data on replication different tissues both ex vivo models.

Language: Английский

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