Pharmacoidea Ltd., 6726 Szeged, Hungary.
Albert Szent-Györgyi Clinical Center, Department of Medicine, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary.
Int J Mol Sci. 2022 Jan 12;23(2):796. doi: 10.3390/ijms23020796.
Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta's spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike's molecular interactions with syndecan-4 also involve syndecan-4's cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta's cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant's spread.
新兴的 SARS-CoV-2 变体对 COVID-19 疫苗接种运动构成威胁。与原始病毒相比，SARS-CoV-2 的 B.1.617 谱系（称为 Delta 变体）更具传染性，于 2021 年席卷全球。Delta 刺突蛋白中的突变使该蛋白向净正静电势方向移动。为了了解 Delta 感染的关键分子驱动因素，我们研究了 Delta 刺突蛋白和带有 Delta 刺突的 SARS-CoV-2 假病毒的细胞摄取。通过对 ACE2 和 syndecan 表达进行特定的体外修饰，我们证明了 syndecan-4（肺中丰富的 syndecan 同工型）通过附着其突变的刺突糖蛋白并促进其细胞进入来增强 Delta 变体的传播。与野生型刺突相比，Delta 刺突对肝素硫酸蛋白聚糖的亲和力高于 ACE2。除了与带负电荷的肝素硫酸链结合外，Delta 刺突与 syndecan-4 的分子相互作用还涉及介导细胞间粘附的 syndecan-4 的细胞结合结构域。无论这些相互作用的复杂性如何，外源性添加的肝素都能像 syndecan-4 敲低一样有效地阻止 Delta 的细胞进入。因此，对 Delta 感染背后的分子机制的深刻理解能够开发出针对分子的简单策略，以减少 Delta 变体的传播。
