Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination

Abstract

The four dengue virus serotypes (DENV1 to DENV4) are mosquito-borne flaviviruses that cause up to ~100 million cases of dengue annually worldwide. Severe disease is thought to result from immunopathogenic processes involving serotype cross-reactive antibodies and T cells that together induce vasoactive cytokines, causing vascular leakage that leads to shock. However, no viral proteins have been directly implicated in triggering endothelial permeability, which results in vascular leakage. DENV nonstructural protein 1 (NS1) is secreted and circulates in patients' blood during acute infection; high levels of NS1 are associated with severe disease. We show that inoculation of mice with DENV NS1 alone induces both vascular leakage and production of key inflammatory cytokines. Furthermore, simultaneous administration of NS1 with a sublethal dose of DENV2 results in a lethal vascular leak syndrome. We also demonstrate that NS1 from DENV1, DENV2, DENV3, and DENV4 triggers endothelial barrier dysfunction, causing increased permeability of human endothelial cell monolayers in vitro. These pathogenic effects of physiologically relevant amounts of NS1 in vivo and in vitro were blocked by NS1-immune polyclonal mouse serum or monoclonal antibodies to NS1, and immunization of mice with NS1 from DENV1 to DENV4 protected against lethal DENV2 challenge. These findings add an important and previously overlooked component to the causes of dengue vascular leak, identify a new potential target for dengue therapeutics, and support inclusion of NS1 in dengue vaccines.

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

“…Importantly, a dose-dependent release of proinflammatory cytokines, such as IL-6 and TNF-α, was observed in the S.Int. of the AG129 mouse model (35,36) in these studies. These observations support the present study, irrespective of whether AG129 mice were infected with a mouseadapted strain (17) or clinical isolate of DENV2 (11).…”

“…Recently, two independent studies reported the potential for the virus-encoded NS1 protein to directly contribute to dengue disease pathogenesis (35,36). The study by Modhiran and colleagues (35,36) demonstrated that NS1 is a pathogen-associated molecular pattern that recognizes TLR4 in target cells, which can lead to release of proinflammatory cytokines.…”

“…The study by Modhiran and colleagues (35,36) demonstrated that NS1 is a pathogen-associated molecular pattern that recognizes TLR4 in target cells, which can lead to release of proinflammatory cytokines. The study by Beatty and colleagues (35,36) showed that NS1 (n = 6 mice/group, orange squares) at day 2 after DENV2. Results are representative of 2 independent experiments.…”

Synergistic Effect of TNF-α and Dengue Virus Infection on Adhesion Molecule Reorganization in Human Endothelial Cells

“…Kanlaya et al also proposed that decreasing levels of vascular endothelial cadherin and Zonula occludens-1 in addition with alteration of actin assembly might be responsible for increased permeability in dengue virus-infected human endothelial cells (11). Recently, it was reported that treatment for recombinant dengue NS1 produced from human embryonic kidney 293 cells in human endothelial cell monolayers (HPMECs and HUVECs) caused disruption of endothelial cell permeability in a dose-and time-dependent manner (28). The authors also suggested that this effect might have been derived from the hexameric NS1 produced from eukaryotic cells.…”

Advances in Dengue Vaccine: A Review Study

“…It has also been reported that it generated lots of cross-reactive nonneutralzing/ enhancing antibodies. It has therefore been proposed that it is not only the presence of dengue neutralizing antibodies that may hold the key to a successful dengue vaccine candidate but also DENV serotype-specific neutralizing antibodies [44,45]. Therefore an effective dengue vaccine must be designed with the capability of inducing predominantly serotype-specific neutralizing antibodies (protective) in the absence of serotype cross-reactive neutralizing antibodies (disease enhancing) [46].…”