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Rapid endotheliitis and vascular damage characterize SARS-CoV-2 infection in a human lung-on-chip model.
Thacker, Vivek V; Sharma, Kunal; Dhar, Neeraj; Mancini, Gian-Filippo; Sordet-Dessimoz, Jessica; McKinney, John D.
  • Thacker VV; Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Sharma K; Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Dhar N; Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Mancini GF; Histology Core Facility, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Sordet-Dessimoz J; Histology Core Facility, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • McKinney JD; Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
EMBO Rep ; 22(6): e52744, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1389837
ABSTRACT
Severe cases of SARS-CoV-2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell-mediated cytokine storm remain unknown. Using a vascularized lung-on-chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro-coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL-6 secretion even in the absence of immune cells. Inhibition of IL-6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS-CoV-2-mediated endothelial cell damage thus occurs independently of cytokine storm.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: EMBO Rep Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: EMBR.202152744

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: EMBO Rep Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: EMBR.202152744