Targeting the Entry Pathway of New World Arenaviruses for Anitviral Threraputics

在上一期PSW RCE的资助中，我们研究了新的 世界B分支阿雷纳病毒。ArenaVirus家族的这个亚群包含5种新出现的人类病原体，能够引起严重的出血热。由于B分支既包含致病成员又包含非致病成员，它已被证明是一个强大的系统，可以用来阐明人类致病性的决定因素。我们已经确定了两组之间的几个关键差异，包括人类转铁蛋白受体1(TfR1)只被人类病原体用作细胞受体的事实。这表明病毒糖蛋白(GP)-TfR1的相互作用对于B分支病毒感染人类的能力可能是非常重要的。这一发现有几点启示：(1)GP和TfR1之间的相互作用很可能是一个很好的治疗靶点，(2)任何新发现的B分支病毒使用TfR1的能力可能是一个很好的人类致病潜力预测因子，以及(3)将抗病毒药物靶向表达TfR1的细胞可能会促进将治疗药物输送到病毒优先感染的相同细胞。TfR1并不是ArenaVirus使用的唯一细胞受体。在此之前，α-肌营养不良聚糖被证明在包括旧世界和新世界分支C病毒在内的几种阿拉伯病毒的进入途径中发挥着重要作用，我们自己的数据表明这个家族至少使用了另外两个未知的受体。ArenaVirus内这种受体选择的灵活性表明，这些病毒可能会继续朝着允许其他物种跳跃进入人类的方向进化。我们未来5年的资助目标是继续对新大陆阿拉伯病毒受体的使用情况建立更完整的图景，并在抗阿拉伯病毒疗法的开发中利用这些信息，包括TfR1靶向siRNA纳米颗粒。同时，我们将开发更好的BSL-2动物模型，用来评估这些试剂的有效性。

In the previous period of funding by the PSW RCE, we have studied the entry pathways used by the New World clade B arenaviruses. This sub-group of the Arenavirus family contains 5 emerging human pathogens, capable of causing severe hemorrhagic fevers. Since clade B contains both pathogenic and non-pathogenic members, it has proved to be a powerful system with which to elucidate the determinants of human pathogenicity. We have identified several key differences between the two groups, including the fact that human transferrin receptor 1 (TfR1) is only used as a cellular receptor by the human pathogens. This suggests that the virus glycoprotein (GP)-TfR1 interaction is likely of great importance for the ability of clade B arenaviruses to infect humans. This finding has several implications: (1) it is likely that the interaction between GP and TfR1 will represent a good therapeutic target, (2) the ability of any newly discovered clade B arenaviruses to use TfR1 may be a good predictor of human pathogenic potential, and (3) targeting antiviral drugs to cells that express TfR1 may promote the delivery of therapeutics to the same cells that the viruses preferentially infect. TfR1 is not the only cellular receptor to be used by the arenaviruses. Previously, a-dystroglycan was shown to play an important role in the entry pathway of several arenaviruses, including Old World and New World clade C viruses, and our own data indicates that at least 2 other unknown receptors are used by this family. Such receptor choice flexibility within the arenaviruses suggests that these viruses could continue to evolve in directions that would allow other species-jumping events into humans. Our goals for the next 5 years of funding are to continue to build a more complete picture of receptor use by the New World arenaviruses, and to exploit this information in the development of anti-arenaviral therapeutics, including TfR1-targeted siRNA nanoparticles. Simultaneously, we will develop better BSL-2 animal models with which to evaluate the effectiveness of these reagents.