人类多瘤病毒的无症状感染很常见,但是这些小病毒可以在免疫受损的宿主中引起严重的疾病。新泽西多瘤病毒(NJPyV)通过肌肉活检在器官移植受者的全身性血管炎中发现,肌炎,和视网膜失明,在人肝组织中检测到人多瘤病毒12(HPyV12)。这两种病毒的进化起源和潜在疾病都没有得到很好的理解。为了定义它们的受体参与策略,我们首先使用核磁共振(NMR)光谱来确定两种病毒的主要衣壳蛋白(VP1)与溶液中的唾液酸结合。然后,我们单独解析了NJPyV和HPyV12VP1的晶体结构以及与唾液酸化聚糖的复合物。NJPyV为α2,3-连接的唾液酸采用了新的结合位点,而HPyV12在暴露部位参与末端α2,3-或α2,6-连接的唾液酸,类似于在棘突毛囊发育相关多瘤病毒(TSPyV)中发现的。神经节苷脂或糖蛋白,在哺乳动物中通常是末端唾液酸,因此是两种病毒的受体候选物。结构分析表明,NJPyV的唾液酸结合位点在黑猩猩多瘤病毒(ChPyV)中是保守的,并且HPyV12的唾液酸结合位点在整个多瘤病毒家族中被广泛使用,包括哺乳动物和禽类多瘤病毒。与其他多瘤病毒-受体复合物结构的比较表明,它们的衣壳已经进化产生几个物理上不同的病毒特异性受体结合位点,这些位点都可以通过有限数量的接触特异性地接合唾液酸化的聚糖。在多瘤病毒的进化过程中,每个站点的微小变化可能已经启用了主机切换事件。重要性病毒附着于细胞表面受体对于生产性感染至关重要。在这项研究中,我们使用基于结构的方法研究了新泽西多瘤病毒(NJPyV)和人类多瘤病毒12(HPyV12)的细胞表面识别事件.这些病毒属于多瘤病毒家族,其成员靶向不同的组织和宿主,包括哺乳动物,鸟,鱼,和无脊椎动物。多瘤病毒是无包膜病毒,受体结合位点位于其衣壳蛋白VP1中。NJPyV衣壳具有新的唾液酸结合位点,该位点与其他结构特征的多瘤病毒相比发生了变化,但与紧密相关的猿猴病毒共享。相比之下,HPyV12VP1以类似于人类毛囊发育不良与多瘤病毒的方式接合末端唾液酸。我们基于结构的系统发育分析强调,即使是远亲的禽类多瘤病毒也具有相同的暴露唾液酸结合位点。这些发现补充了宿主病毒共异的系统发育模型,也可能反映了过去的宿主转换事件。
Asymptomatic infections with polyomaviruses in humans are common, but these small viruses can cause severe diseases in immunocompromised hosts. New Jersey polyomavirus (NJPyV) was identified via a muscle biopsy in an organ transplant recipient with systemic vasculitis, myositis, and retinal blindness, and human polyomavirus 12 (HPyV12) was detected in human liver tissue. The evolutionary origins and potential diseases are not well understood for either virus. In order to define their receptor engagement strategies, we first used nuclear magnetic resonance (NMR) spectroscopy to establish that the major capsid proteins (VP1) of both viruses bind to sialic acid in solution. We then solved crystal structures of NJPyV and HPyV12 VP1 alone and in complex with sialylated glycans. NJPyV employs a novel binding site for a α2,3-linked sialic acid, whereas HPyV12 engages terminal α2,3- or α2,6-linked sialic acids in an exposed site similar to that found in Trichodysplasia spinulosa-associated polyomavirus (TSPyV). Gangliosides or glycoproteins, featuring in mammals usually terminal sialic acids, are therefore receptor candidates for both viruses. Structural analyses show that the sialic acid-binding site of NJPyV is conserved in chimpanzee polyomavirus (ChPyV) and that the sialic acid-binding site of HPyV12 is widely used across the entire polyomavirus family, including mammalian and avian polyomaviruses. A comparison with other polyomavirus-receptor complex structures shows that their capsids have evolved to generate several physically distinct virus-specific receptor-binding sites that can all specifically engage sialylated glycans through a limited number of contacts. Small changes in each site may have enabled host-switching events during the evolution of polyomaviruses.IMPORTANCE Virus attachment to cell surface receptors is critical for productive infection. In this study, we have used a structure-based approach to investigate the cell surface recognition event for New Jersey polyomavirus (NJPyV) and human polyomavirus 12 (HPyV12). These viruses belong to the polyomavirus family, whose members target different tissues and hosts, including mammals, birds, fish, and invertebrates. Polyomaviruses are nonenveloped viruses, and the receptor-binding site is located in their capsid protein VP1. The NJPyV capsid features a novel sialic acid-binding site that is shifted in comparison to other structurally characterized polyomaviruses but shared with a closely related simian virus. In contrast, HPyV12 VP1 engages terminal sialic acids in a manner similar to the human Trichodysplasia spinulosa-associated polyomavirus. Our structure-based phylogenetic analysis highlights that even distantly related avian polyomaviruses possess the same exposed sialic acid-binding site. These findings complement phylogenetic models of host-virus codivergence and may also reflect past host-switching events.