Details

Autor(en) / Beteiligte

• Puerta-Guardo, Henry
• Glasner, Dustin R.
• Espinosa, Diego A.
• Biering, Scott B.
• Patana, Mark
• Ratnasiri, Kalani
• Wang, Chunling
• Beatty, P. Robert
• Harris, Eva

Titel

Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism

Ist Teil von

• Cell reports (Cambridge), 2019-02, Vol.26 (6), p.1598-1613.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •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 Puerta-Guardo et al. discover that five flavivirus NS1 proteins trigger hyperpermeability and vascular dysfunction in human endothelial cells and mice in a manner reflecting disease tropism. This tissue-specific tropism is partially determined by the capacity of NS1 to bind endothelial cells and is characterized by disruption of endothelial glycocalyx components.