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

Abstract

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.

The dengue virus non-structural protein 1 (NS1) use the scavenger receptor B1 as cell receptor in human hepatic and mosquito cells

“…Likewise, different fluoresce patters were observed between internalized DENV and ZIKV NS1 in liver cells, with ZIKV NS1 showing a fiber-like pattern. These observations, in agreement with previous data (Puerta-Guardo, et al, 2019), suggest that there may be cell and virus dependent differences in the way NS1 is internalized.…”

“…In this work, we assessed the participation of the SRB1 as a receptor of the DENV and ZIKV NS1 in human hepatic and insect cells. First, we observed the internalization of DENV and ZIKV NS1 in hepatic cells as previously reported (Alcon-Le Poder et al, 2005, Puerta-Guardo et al, 2019). Additionally, we observed that NS1 internalization also occurs in insect cells.…”

“…It has been reported NS1 can affect the complement pathway promoting the degradation of C4 protein, alters the coagulation system inhibiting the activation of prothrombin (reviewed by Conde et al, 2017). NS1 can also disrupts endothelium integrity, promoting an increase in the vascular permeability after internalization by endocytosis, that may be related to plasma leakage (Glasner et al, 2017; Puerta-Guardo et al, 2019; Wang et al, 2019). Moreover, pre-exposure of human liver or dendritic cells to NS1 renders these cells more susceptible to DENV replication (Alcon-LePoder et al, 2005; Alayli and Scholle, 2016).…”

Relative contribution of nonstructural protein 1 in dengue pathogenesis

“…D2Y98P virulence is independent of the intrinsic ability of NS1 to increase vascular permeability. Absence of NS1-mediated protective immunity and the lack of increased vascular leakage observed upon exogenous administration of NS1(D2Y98P) to sublethally infected mice prompted us to test the ability of purified NS1(D2Y98P) to interact and disrupt the endothelial integrity compared with NS1 from DENV2 strain 16681 recently reported to be vascular leak potent (Puerta-Guardo et al, 2019). Two different in vitro permeability assays were conducted, namely transendothelial electrical resistance (TEER) assay and real-time cell analysis (RTCA), as previously described (Chen et al, 2016).…”

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade

“…Besides structural proteins incorporated into viral particles, another membrane associated glycoprotein NS1 can also be secreted extracellularly as hexamers, and detected in blood during acute infection. The NS1 protein can cause pathology in humans through either altering endothelial permeability or inducing antibodies that cross-react with host endothelial proteins; it can also facilitate viral transmission in mosquitoes through antagonizing mosquito innate immunity via suppressing the expression of immune-related genes involved in ROS and JAK/STAT pathways (Liu et al, 2011;Puerta-Guardo et al, 2019). Consistently, antibodies to NS1 can protect mice from lethal diseases in experimental models (Wan et al, 2017;Bailey et al, 2018).…”