Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro

Abstract

Ebola virus (EBOV) causes a highly lethal hemorrhagic fever syndrome in humans and has been associated with mortality rates of up to 91% in Zaire, the most lethal strain. Though the viral envelope glycoprotein (GP) mediates widespread inflammation and cellular damage, these changes have mainly focused on alterations at the protein level, the role of microRNAs (miRNAs) in the molecular pathogenesis underlying this lethal disease is not fully understood. Here, we report that the miRNAs hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p were induced in human umbilical vein endothelial cells (HUVECs) following expression of EBOV GP. Among the proteins encoded by predicted targets of these miRNAs, the adhesion-related molecules tissue factor pathway inhibitor (TFPI), dystroglycan1 (DAG1) and the caspase 8 and FADD-like apoptosis regulator (CFLAR) were significantly downregulated in EBOV GP-expressing HUVECs. Moreover, inhibition of hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p, or overexpression of TFPI, DAG1 and CFLAR rescued the cell viability that was induced by EBOV GP. Our results provide a novel molecular basis for EBOV pathogenesis and may contribute to the development of strategies to protect against future EBOV pandemics. Ebola virus, glycoprotein, microRNAs, cytotoxicity Citation:Sheng MM, Zhong Y, Chen Y, Du JC, Ju XW, Zhao C, Zhang GG, Zhang LF, Liu KT, Yang N, Xie P, Li DS, Zhang MQ, Jiang CY. Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro. Sci China Life Sci, 2014, 57: 959 -972,

Ebola from emergence to epidemic: the virus and the disease, global preparedness and perspectives

“…However, the major drawback with such potential drug regimens is the requirement of multiple doses for achieving the proper therapeutic efficacy, which is not ideal with regard to patient compliance and outbreak scenarios [66]. The microRNA (mi-RNAs: hsa-miR-1246, hsa-miR-320a, and hsa-miR-196b-5p) inhibitors have also been suggested to lower the cytotoxicity of Ebola virus glycoprotein in in vitro trials [76]. Nevertheless, more studies are needed before the final clearance and launch of any safe and efficacious antiviral drug in the global market, as considerable differences exist in the defence systems of human and small animal models, and therefore, the results of animal experimentations cannot be directly extrapolated for human beings.…”

Non-coding regions of the Ebola virus genome contain indispensable phylogenetic and evolutionary information

“…The GP protein of EBOV is responsible for receptor binding and fusion of the viral and cellular membranes. Recently, it has been reported to be able to mediate the level of certain microRNAs [3], which could be served as potential targets for Ebola drugs. Phylogenic analyses were performed using a Bayesian evolutionary analysis by sampling trees (Beast) approach [4], and 24 different combinations of molecular clock models (n=3) and coalescent models (n=8) were applied (Table S2 in Supporting Information).…”

MicroRNAs: the novel targets for Ebola drugs

“…GP is considered as a viral determinant of EBOV pathogenicity and likely contributes to hemorrhage during infection, as several groups reported that overexpression of GP can induce cell detachment and rounding in vitro and ex vivo [2]. Similar results were also confirmed by Prof. Jiang and her colleagues [3].…”

“…In the article published in this issue, Sheng et al [3] attempted to explore the molecule mechanism by which GP induces cell damage from a new angle. They evaluated the microRNA levels, using the RNA-Seq method, in human umbilical endothelial cells (HUVECs) that overexpress EBOV GP.…”

“…In general, they silence the expression of their target genes via degradation of the mRNA or by translational repression. In the paper of Sheng et al [3], the target genes of hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p were predicted using the miRDB database. They further analyzed the expression levels of those genes in the GP-expressing cells by Western blotting and found that seven out of 21 predicted genes were down-regulated comparing with the negative controls.…”