Dengue Viral Protease Interaction with NF-κB Inhibitor α/β Results in Endothelial Cell Apoptosis and Hemorrhage Development

Abstract

Hemorrhagic manifestations occur frequently accompanying a wide range of dengue disease syndromes. Much work has focused on the contribution of immune factors to the pathogenesis of hemorrhage, but how dengue virus (DENV) participates in the pathogenic process has never been explored. Although there is no consensus that apoptosis is the basis of vascular permeability in human dengue infections, we showed in dengue hemorrhage mouse model that endothelial cell apoptosis is important to hemorrhage development in mice. To explore the molecular basis of the contribution of DENV to endothelial cell death, we show in this study that DENV protease interacts with cellular IκBα and IκBβ and cleaves them. By inducing IκBα and IκBβ cleavage and IκB kinase activation, DENV protease activates NF-κB, which results in endothelial cell death. Intradermal inoculation of DENV protease packaged in adenovirus-associated virus-9 induces endothelial cell death and dermal hemorrhage in mice. Although the H51 activity site is not involved in the interaction between DENV protease and IκB-α/β, the enzymatic activity is critical to the ability of DENV protease to induce IκBα and IκBβ cleavage and trigger hemorrhage development. Moreover, overexpression of IκBα or IκBβ protects endothelial cells from DENV-induced apoptosis. In this study, we show that DENV protease participates in the pathogenesis of dengue hemorrhage and discover IκBα and IκBβ to be the new cellular targets that are cleaved by DENV protease.

Anti-TNF-α restricts dengue virus-induced neuropathy

“…For DENV‐induced TNF‐α production, our previous studies showed the potential regulation of TNF‐α production by DENV‐activated NF‐κB independent of TLR 3 signaling. Additionally, forced expression of the NS2B3 viral protein enhances DENV‐induced TNF‐α production probably by activating NF‐κB, whereas NS2B3 is shown as an activator of NF‐κB for inflammatory activation and hemorrhagic responses . We also demonstrated that DENV infection causes activation of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2), an essential regulator of antioxidant response, to increase C‐type lectin domain family 5, member A (CLEC5A) expression for TNF‐α production .…”

Characterization of cytopathic factors through genome-wide analysis of the Zika viral proteins in fission yeast

“…Early sequence and structural comparisons of the ZIKV E protein with that of other flaviviruses suggest that overall the ZIKV E protein is unique among flaviviruses, although parts of it resemble its homologs in WNV, JEV, or DENV (64,65). During flaviviral assembly, E interacts with prM to form the prM-E heterodimers that protrude from the viral surface in the noninfectious and immature viral particles (25). It also is involved in fusing the viral membrane with the host endosome membrane.…”

“…In DENV, E protein forms a heterodimer with prM and affects viral particle formation and secretion (25). The resultant noninfectious and immature viral particles are transported through the TGN, where prM is cleaved by a host protease Furin, resulting in mature infectious particles (26,27).…”

Endothelial dysfunction in dengue virus pathology

“…Apoptosis and structural alterations in DENVinfected ECs. Although apoptotic ECs are rarely observed in tissues from fatal DHF/DSS [22], Lin et al [111] recently showed that intradermal inoculation of the DENV protease in mice induces endothelial cell death and dermal hemorrhage by cleavage of the nuclear factor kappa B (NF-κB) inhibitor IκB α/β. Overexpression of IκBα or IκBβ protected ECs from DENV-induced apoptosis, suggesting that the NF-κB pathway may contribute to vascular permeability in DENV infections.…”