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The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Κ18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells.
Colunga Biancatelli, Ruben M L; Solopov, Pavel A; Sharlow, Elizabeth R; Lazo, John S; Marik, Paul E; Catravas, John D.
  • Colunga Biancatelli RML; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia.
  • Solopov PA; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia.
  • Sharlow ER; Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia.
  • Lazo JS; Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, Virginia.
  • Marik PE; Division of Pulmonary Disease and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, Virginia.
  • Catravas JD; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, Virginia.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L477-L484, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1376529
ABSTRACT
Acute lung injury (ALI) leading to acute respiratory distress syndrome is the major cause of COVID-19 lethality. Cell entry of SARS-CoV-2 occurs via the interaction between its surface spike protein (SP) and angiotensin-converting enzyme-2 (ACE2). It is unknown if the viral spike protein alone is capable of altering lung vascular permeability in the lungs or producing lung injury in vivo. To that end, we intratracheally instilled the S1 subunit of SARS-CoV-2 spike protein (S1SP) in K18-hACE2 transgenic mice that overexpress human ACE2 and examined signs of COVID-19-associated lung injury 72 h later. Controls included K18-hACE2 mice that received saline or the intact SP and wild-type (WT) mice that received S1SP. K18-hACE2 mice instilled with S1SP exhibited a decline in body weight, dramatically increased white blood cells and protein concentrations in bronchoalveolar lavage fluid (BALF), upregulation of multiple inflammatory cytokines in BALF and serum, histological evidence of lung injury, and activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways in the lung. K18-hACE2 mice that received either saline or SP exhibited little or no evidence of lung injury. WT mice that received S1SP exhibited a milder form of COVID-19 symptoms, compared with the K18-hACE2 mice. Furthermore, S1SP, but not SP, decreased cultured human pulmonary microvascular transendothelial resistance (TER) and barrier function. This is the first demonstration of a COVID-19-like response by an essential virus-encoded protein by SARS-CoV-2 in vivo. This model of COVID-19-induced ALI may assist in the investigation of new therapeutic approaches for the management of COVID-19 and other coronaviruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cell Membrane Permeability / Endothelial Cells / Acute Lung Injury / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 / Lung Topics: Long Covid Limits: Animals / Humans / Male Language: English Journal: Am J Physiol Lung Cell Mol Physiol Journal subject: Molecular Biology / Physiology Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Cell Membrane Permeability / Endothelial Cells / Acute Lung Injury / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 / Lung Topics: Long Covid Limits: Animals / Humans / Male Language: English Journal: Am J Physiol Lung Cell Mol Physiol Journal subject: Molecular Biology / Physiology Year: 2021 Document Type: Article