Abstract
The Flaviviridae contain numerous medically important human pathogens that cause potentially life-threatening infections. Over half of the world's population is at risk of flavivirus infection, and this number is expected to increase as climate change expands the habitats of the arthropod vectors that transmit these flaviviruses. There are few effective vaccines and no therapeutics approved for prevention or treatment of flavivirus infection, respectively. Given these challenges, understanding how and why flaviviruses cause pathogenesis is critical for identifying targets for therapeutic intervention. The secreted nonstructural protein 1 (NS1) of flaviviruses is a conserved virulence factor that triggers endothelial dysfunction in a tissue-specific manner. It is unknown if this endothelial dysfunction provides any benefit for virus infection. Here we provide evidence that NS1-triggered endothelial dysfunction facilitates virus crossing of endothelial barriers and augments infection of target cells in vitro and promotes virus dissemination in vivo . This study provides an evolutionary explanation for flaviviruses evolving the capacity to trigger barrier dysfunction and highlights NS1 and the pathways governing endothelial dysfunction, as therapeutic targets to prevent flavivirus dissemination.
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