近日，美国弗雷德·哈钦森癌症中心Jesse D. Bloom及其小组发现，深度突变扫描揭示拉沙病毒糖蛋白复合物的功能限制和抗体逃逸潜力。2024年7月15日，国际知名学术期刊《免疫》在线发表了这一成果。

为描绘拉沙病毒糖蛋白复合物（GPC）的演化空间可及性，研究人员使用假病毒深度突变扫描测量了几乎所有GPC氨基酸突变对细胞进入和抗体中和的影响。实验定义了GPC整个结构的功能限制，并量化了GPC突变对一组单克隆抗体中和作用的影响。所有测试的抗体都被自然存在的拉沙病毒谱系中的突变所逃逸。总体而言，这项研究描述了一种生物安全二级方法，阐明了GPC的可变突变空间，并展示了前瞻性抗原变异特征如何有助于治疗和疫苗设计。

研究人员表示，拉沙病毒每年估计导致数千人死亡，主要是由于其自然宿主多乳鼠传播的结果。在研制疫苗和抗体疗法的过程中，必须考虑到拉沙病毒GPC的演化变异性，GPC介导病毒进入细胞，并且是中和抗体的靶点。

附：英文原文

Title: Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex

Author: Caleb R. Carr, Katharine H.D. Crawford, Michael Murphy, Jared G. Galloway, Hugh K. Haddox, Frederick A. Matsen, Kristian G. Andersen, Neil P. King, Jesse D. Bloom

Issue&Volume: 2024-07-15

Abstract: Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.

DOI: 10.1016/j.immuni.2024.06.013

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00319-4