Targeting the Entry Pathway of New World Arenaviruses for Anitviral Threraputics

在PSW RCE的上一个资助期间，我们研究了新的入学途径， 世界分支B沙粒病毒。沙粒病毒家族的这个亚组包含5种新出现的人类病原体，能够引起严重的出血热。由于进化枝B包含致病性和非致病性成员，它已被证明是一个强大的系统，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，包括人转铁蛋白受体1（TfR 1）仅被人类病原体用作细胞受体的事实。这表明病毒糖蛋白（GP）-TfR 1相互作用可能对进化枝B沙粒病毒感染人类的能力非常重要。这一发现有几个含义：（1）GP和TfR 1之间的相互作用可能代表良好的治疗靶点，（2）任何新发现的进化枝B沙粒病毒利用TfR 1的能力可能是人类致病潜力的良好预测因子，以及（3）将抗病毒药物靶向表达TfR 1的细胞可能会促进治疗药物递送到病毒优先感染的相同细胞。TfR 1不是沙粒病毒唯一使用的细胞受体。以前，α-肌营养不良蛋白聚糖被证明在几种沙粒病毒的进入途径中起重要作用，包括旧世界和新世界C进化枝病毒，我们自己的数据表明该家族使用至少2种其他未知受体。沙粒病毒中这种受体选择的灵活性表明，这些病毒可以继续向允许其他物种跳跃事件进入人类的方向进化。我们未来5年的资助目标是继续建立新世界沙粒病毒受体使用的更完整的图片，并利用这些信息开发抗沙粒病毒疗法，包括TfR 1靶向siRNA纳米颗粒。同时，我们将开发更好的BSL-2动物模型，以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.