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Asprellcosides B of Ilex asprella Inhibits Influenza A Virus Infection by Blocking the Hemagglutinin- Mediated Membrane Fusion.

ABSTRACT: Ilex asprella is routinely used in China as a traditional medicinal herb to treat influenza (Flu). However, its specific antiviral activity and underlying molecular mechanism have not yet been determined. In this study, we sought to determine the antiviral activity and mechanism of Asprellcosides B, an active component extracted from Ilex asprella, and used against the influenza A virus cell culture. We also performed a computer-assisted structural modeling analysis and carried out surface plasmon resonance (SPR) experiments in the hope of determining the viral target of Asprellcosides B. Results from our studies show that Asprellcosides B reduced virus replication by up to 63% with an IC50 of about 9 ?M. It also decreased the low pH-induced and virus-mediated hemolysis by 71% in vitro. Molecular docking simulation analysis suggested a possible binding of Asprellcosides B to the hemagglutinin (HA), which was confirmed by a surface plasmon resonance (SPR) assay. Altogether, our findings demonstrate that Asprellcosides B inhibits the influenza A virus, through a specific binding to the HA, resulting in the blockade of the HA-mediated membrane fusion.

SUBMITTER: Zhang W

PROVIDER: S-EPMC6351491 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Asprellcosides B of Ilex asprella Inhibits Influenza A Virus Infection by Blocking the Hemagglutinin- Mediated Membrane Fusion.

Zhang Wen W Chen Si-Tai ST He Qiu-Yan QY Huang Li-Quan LQ Li Xiong X Lai Xiao-Ping XP Zhan Shao-Feng SF Huang Hui-Ting HT Liu Xiao-Hong XH Wu Jianguo J Li Geng G

Frontiers in microbiology 20190123

Ilex asprella is routinely used in China as a traditional medicinal herb to treat influenza (Flu). However, its specific antiviral activity and underlying molecular mechanism have not yet been determined. In this study, we sought to determine the antiviral activity and mechanism of Asprellcosides B, an active component extracted from Ilex asprella, and used against the influenza A virus cell culture. We also performed a computer-assisted structural modeling analysis and carried out ...[more]

PMID: 30728818

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Project description:The highly conserved cytoplasmic tail of influenza virus glycoprotein hemagglutinin (HA) contains three cysteines, posttranslationally modified by covalently bound fatty acids. While viral HA acylation is crucial in virus replication, its physico-chemical role is unknown. We used virus-like particles (VLP) to study the effect of acylation on morphology, protein incorporation, lipid composition, and membrane fusion. Deacylation interrupted HA-M1 interactions since deacylated mutant HA failed to incorporate an M1 layer within spheroidal VLP, and filamentous particles incorporated increased numbers of neuraminidase (NA). While HA acylation did not influence VLP shape, lipid composition, or HA lateral spacing, acylation significantly affected envelope curvature. Compared to wild-type HA, deacylated HA is correlated with released particles with flat envelope curvature in the absence of the matrix (M1) protein layer. The spontaneous curvature of palmitate was calculated by molecular dynamic simulations and was found to be comparable to the curvature values derived from VLP size distributions. Cell-cell fusion assays show a strain-independent failure of fusion pore enlargement among H2 (A/Japan/305/57), H3 (A/Aichi/2/68), and H3 (A/Udorn/72) viruses. In contradistinction, acylation made no difference in the low-pH-dependent fusion of isolated VLPs to liposomes: fusion pores formed and expanded, as demonstrated by the presence of complete fusion products observed using cryo-electron tomography (cryo-ET). We propose that the primary mechanism of action of acylation is to control membrane curvature and to modify HA's interaction with M1 protein, while the stunting of fusion by deacylated HA acting in isolation may be balanced by other viral proteins which help lower the energetic barrier to pore expansion.IMPORTANCE Influenza A virus is an airborne pathogen causing seasonal epidemics and occasional pandemics. Hemagglutinin (HA), a glycoprotein abundant on the virion surface, is important in both influenza A virus assembly and entry. HA is modified by acylation whose removal abrogates viral replication. Here, we used cryo-electron tomography to obtain three-dimensional images to elucidate a role for HA acylation in VLP assembly. Our data indicate that HA acylation contributes to the capability of HA to bend membranes and to HA's interaction with the M1 scaffold protein during virus assembly. Furthermore, our data on VLP and, by hypothesis, virus suggests that HA acylation, while not critical to fusion pore formation, contributes to pore expansion in a target-dependent fashion.

Dataset Information

Asprellcosides B of Ilex asprella Inhibits Influenza A Virus Infection by Blocking the Hemagglutinin- Mediated Membrane Fusion.

Publications

Asprellcosides B of <i>Ilex asprella</i> Inhibits Influenza A Virus Infection by Blocking the Hemagglutinin- Mediated Membrane Fusion.

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