Prospectively characterizing the functional and antigenic effects of mutations to viral entry proteins

病毒对人类健康构成持续威胁，在很大程度上是因为 它们进入蛋白的进化。这种进化可以使病毒感染新物种。 (包括人类)，并逃避基于抗体的免疫。我们将整合 从基因组学、计算和病毒学到前瞻性开发通用平台的方法 描述病毒进入蛋白的突变如何影响其感染能力 细胞，并抵抗抗体的中和。该平台可以用来研究 非常广泛的病毒的进入蛋白。我们将用它来描述这些影响 在来自四种重要新兴病毒的进入蛋白的所有氨基酸突变中： 埃博拉病毒、MERS冠状病毒、拉萨病毒和尼帕病毒。我们将全面识别 影响这些病毒感染相关寄主物种细胞的能力的突变，以及 利用这些结果，算法可以根据序列来评估病毒的宿主适应性。我们 还将开发利用该平台的算法，以量化所有突变如何 病毒进入蛋白影响其对抗体免疫的敏感性。总体而言，这项工作 开发了一种强大而通用的方法来前瞻性地表征病毒的含义 突变。

Viruses pose a constant threat to human health in substantial part because of the evolution of their entry proteins. This evolution can enable viruses to infect new species (including humans), and to evade antibody-based immunity. We will integrate approaches from genomics, computation, and virology to develop a general platform to prospectively characterize how mutations to a virus's entry protein affect its ability to infect cells and resist neutralization by antibodies. This platform can be used to study the entry proteins of an extremely wide range of viruses. We will use it to characterize the effects of all amino-acid mutations to the entry proteins from four important emerging viruses: Ebola virus, MERS coronavirus, Lassa virus, and Nipah virus. We will comprehensively identify mutations that affect the ability of these viruses to infect cells from relevant host species, and use the results to inform algorithms that assess a virus's host adaptation from sequence. We will also develop algorithms that leverage the platform to quantify how all mutations to a viral entry protein affect its susceptibility to antibody-based immunity. Overall, this work develops a powerful and general method to prospectively characterize the implications of viral mutations.