Ströh Luisa J, Maginnis Melissa S, Blaum Bärbel S, Nelson Christian D S, Neu Ursula, Gee Gretchen V, O'Hara Bethany A, Motamedi Nasim, DiMaio Daniel, Atwood Walter J, Stehle Thilo
Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA Department of Molecular and Biomedical Sciences, University of Maine, Orono, Maine, USA.
J Virol. 2015 Jun;89(12):6364-75. doi: 10.1128/JVI.00489-15. Epub 2015 Apr 8.
The human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidneys of the majority of the population and is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require α2,6-linked sialic acid on the lactoseries tetrasaccharide c (LSTc) glycan for attachment to host cells. In contrast, a JCPyV kidney isolate type 3 strain, WT3, has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and correlated these data with the results of infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement, while the more weakly binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis.
Viral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidneys of the majority of the population and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection.
人类JC多瘤病毒（JCPyV）在大多数人的肾脏中建立无症状的持续性感染，并且是免疫抑制个体中致命性脱髓鞘疾病进行性多灶性白质脑病（PML）的病原体。JCPyV的Mad-1株是一种脑分离株，先前已证明其需要乳糖系列四糖c（LSTc）聚糖上的α2,6-连接唾液酸才能附着于宿主细胞。相比之下，据报道一种JCPyV肾脏分离株3型（WT3）与含唾液酸的神经节苷脂相互作用，但这些聚糖在JCPyV感染中的作用仍不清楚。为了帮助解释这些发现并探究菌株特异性差异对受体结合的影响，我们使用高分辨率X射线晶体学和核磁共振（NMR）光谱对这两种代表性JCPyV菌株的聚糖受体特异性进行了全面分析，并将这些数据与感染性测定结果相关联。我们在此表明，Mad-1和WT3 JCPyV的衣壳蛋白都可以与LSTc以及多种唾液酸化神经节苷脂结合。然而，结合亲和力存在细微差异，对LSTc的亲和力最高。LSTc的结合是功能性受体结合的先决条件，而结合较弱的神经节苷脂并非生产性感染所必需。我们的发现突出了病毒与碳水化合物相互作用的复杂性，并表明结合亲和力的细微差异而非单纯的结合事件有助于确定组织嗜性和病毒发病机制。
病毒感染始于附着于宿主细胞上的受体，这一事件在病毒性疾病中起重要作用。我们研究了人类JC多瘤病毒（JCPyV）的受体结合特性，该病毒存在于大多数人的肾脏中，可在免疫抑制个体的大脑中引起致命性脱髓鞘疾病进行性多灶性白质脑病（PML）。据报道JCPyV与多种碳水化合物受体相互作用，我们试图阐明JCPyV与细胞碳水化合物受体之间的相互作用如何影响感染。在此我们证明JCPyV可以与多种唾液酸化碳水化合物受体结合。然而，该病毒对LSTc表现出优先结合，并且只有LSTc介导生产性感染。我们的发现表明，结合亲和力的细微差异而非单纯的受体结合是病毒感染的关键决定因素。
