HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis-A Pivotal Anti-hantaviral Role of TRAIL.

Qing-Zhou Chen,Yong-Zhen Zhang,Mei-Rong Wang,Ning Li,Fan Luo,Yu-Xing Zan,Hai-Tao Hu,Shuang Lu,Xin Wang,Chao-Jie Zhong,Wei Hou,Hai-Rong Xiong,Ni Zhu

doi:10.3389/fimmu.2020.01072

Abstract

Hantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and have led to public health threat in China. The pathogenesis of HFRS is complex and involves capillary leakage due to the infection of vascular endothelial cells. Accumulating evidence has demonstrated that hantavirus can induce apoptosis in many cells, but the mechanism remains unclear. Our studies showed that Hantaan virus (HTNV) infection could induce TNF-related apoptosis-inducing ligand (TRAIL) expression in primary human umbilical vein endothelial cells (HUVECs) and sensitize host cells toward TRAIL-mediated apoptosis. Furthermore, TRAIL interference could inhibit apoptosis and enhance the production of HTNV as well as reduce IFN-β production, while exogenous TRAIL treatment showed reverse outcome: enhanced apoptosis and IFN-β production as well as a lower level of viral replication. We also observed that nucleocapsid protein (NP) and glycoprotein (GP) of HTNV could promote the transcriptions of TRAIL and its receptors. Thus, TRAIL was upregulated by HTNV infection and then exhibited significant antiviral activities in vitro, and it was further confirmed in the HTNV-infected suckling mice model that TRAIL treatment significantly reduced viral load, alleviated virus-induced tissue lesions, increased apoptotic cells, and decreased the mortality. In conclusion, these results demonstrate that TRAIL-dependent apoptosis and IFN-β production could suppress HTNV replication and TRAIL treatment might be a novel therapeutic target for HTNV infection.

Highlights

Hantaviruses are enveloped, negative-sense viruses and contain a tripartite RNA genome (S, M, and L segments), which encodes the nucleocapsid protein, glycoproteins (G1 and G2), and the RNA-dependent polymerase protein, respectively [1]
It is worth noting that the distribution of DcR1 and DcR2 in human umbilical vein endothelial cells (HUVECs) surface after Hantaan virus (HTNV) infection show a downward trend, which is consistent with gene and protein results
These results indicated that HTNV infection may promote tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-dependent apoptotic signaling pathway in primary HUVECs

Summary

Introduction

Hantaviruses (family Hantaviridae, order Bunyavirales) are enveloped, negative-sense viruses and contain a tripartite RNA genome (S, M, and L segments), which encodes the nucleocapsid protein, glycoproteins (G1 and G2), and the RNA-dependent polymerase protein, respectively [1]. Researchers further revealed that hantavirus infection interferes with DAXX-mediated apoptosis in ANDVand HTNV-infected HUVECs by activation of the interferonstimulated nuclear transcription factor pro-myelocytic leukemia protein (PML) [12]. Gupta et al demonstrated that HTNV and ANDV [multiplicity of infection (MOI) = 1] inhibited NK cellmediated cytotoxic granule-dependent induction of apoptosis in the endothelial co-cultured with NK cells. They showed that HTNV and ANDV (MOI = 0.01) inhibited staurosporineinduced apoptosis at lower viral titer [17]. The precise mechanism how hantavirus regulates a specific apoptotic response in endothelial cells per se remains obscure

Methods

Results

Conclusion