Transcriptional Responses Induced by Polyomavirus Attachment and Entry

描述（由申请方提供）：DNA病毒在感染开始时经常激活细胞促有丝分裂反应，一旦病毒基因组到达细胞核，该反应会使细胞处于病毒基因组复制的平衡状态。内吞转运和信号转导作为紧密耦合的事件越来越受到重视。因此，病毒与细胞表面的初始相互作用以及在进入过程中，对于最大化病毒产量至关重要。多瘤病毒诱导典型的“早期（血清）应答”基因（即，c-myc，c-fos），并通过其VP 1衣壳蛋白结合充分表征的神经节苷脂受体，其可能参与启动信号转导级联反应。虽然许多病毒与细胞表面聚糖/神经节苷脂受体相互作用，但在细胞进入期间使用基于脂质的信号传导机制可能在病毒发病机制中发挥关键且未被充分认识的作用。利用缺乏糖脂的细胞 修饰和具有影响聚糖和整联蛋白结合的特异性衣壳蛋白突变的配体，我们将表征在多瘤病毒附着和进入期间诱导的转录信号。这些VP 1信号转导的研究可能揭示细胞内信号转导途径，这是病毒在感染过程中接合顺序受体的关键。例如，SV 40/BKV/JCV感染被非特异性酪氨酸激酶抑制剂染料木黄酮阻断，这表明鉴定更特异性的信号传导靶点可能导致多瘤病毒感染的小分子抑制剂的开发。尽管对于免疫功能低下个体中人BKV和JCV感染的治疗可能非常重要，但可以鉴定出其他靶标，其延伸超出多瘤病毒至使用唾液酸聚糖作为附着蛋白的许多其他病毒，从而为抗病毒治疗开辟了新途径。

DESCRIPTION (provided by applicant): DNA viruses frequently activate a cellular mitogenic response at the outset of infection that poises the cell for the replication of the viral genome once it reaches the nucleus. Endocytic transport and signal transduction are increasingly being appreciated as tightly coupled events. Thus, the initial interactions of the virus with the cell surface, as well as during entry, are critical for maximizing virus yields. Polyomaviruses induce typical "early (serum) response" genes (i.e., c-myc, c-fos) upon cell attachment, and via their VP1 capsid protein bind well-characterized ganglioside receptors, which may be involved in initiating the signal transduction cascade. Although many viruses interact with cell surface glycan/ganglioside receptors, the use of lipid-based signaling mechanisms during cell entry may play critical and underappreciated roles in viral pathogenesis. Using cells deficient in glycolipid modifications and ligands with specific capsid protein mutations affecting glycan and integrin binding we will characterize the transcriptional signals induced during polyomavirus attachment and entry. These studies of VP1 signaling may uncover intracellular signaling pathways that are critical to viruses engaging sequential receptors during infection. For example, SV40/BKV/JCV infections are blocked by the non-specific tyrosine kinase inhibitor genistein, suggesting that identifying more specific signaling targets could lead to the development of small molecule inhibitors of polyomavirus infection. Although potentially very significant for the therapy of human BKV and JCV infections in immunocompromised individuals, additional targets may be identified that extend beyond the polyomaviruses to the many other viruses that use sialyl-glycans as attachment proteins, opening new avenues for anti-viral therapy.