Cell Reports
Volume 26, Issue 6, 5 February 2019, Pages 1598-1613.e8
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Article
Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism

https://doi.org/10.1016/j.celrep.2019.01.036Get rights and content
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Highlights

  • Flavivirus NS1 proteins induce endothelial dysfunction in a tissue-specific manner

  • Tissue tropism of 5 NS1 proteins is partly determined by endothelial cell binding

  • NS1-induced endothelial dysfunction is mediated by endothelial glycocalyx disruption

  • Flavivirus NS1 proteins induce tissue-specific leak in mice mirroring viral tropism

Summary

Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development.

Keywords

Flavivirus
dengue virus
Zika virus
West Nile virus
Japanese encephalitis virus
yellow fever virus
NS1
endothelial permeability
vascular leak
disease tropism

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2

These authors contributed equally

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