Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461.
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2100104118.
Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline-revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections.
关节炎相关的甲病毒在全球范围内广泛分布，通过蚊子传播，可导致人类发生风湿性疾病，包括基孔肯雅热病毒（CHIKV）、马亚罗病毒（MAYV）等。虽然血清学证据表明，甲病毒感染可能会提供一些抗体介导的异源免疫，但在自然感染过程中，广泛中和抗体（可预防多种关节炎相关甲病毒）的产生程度仍不清楚。在此，我们描述了从 CHIKV 恢复期供体中分离和鉴定 MAYV 反应性甲病毒单克隆抗体（mAb）的情况。我们鉴定了 33 种与人 CHIKV 和 MAYV 发生交叉反应的人类 mAb，这些 mAb 可与 E1 和 E2 糖蛋白上的多个表位结合。我们鉴定了 5 种靶向 E2 蛋白 B 结构域不同区域的 mAb，这些 mAb 可强力中和多种甲病毒，且抑制范围存在差异。这些广泛中和 mAb（bNAb）含有较少的体细胞突变，推断的种系回复突变体保留了中和能力。两种 bNAb，DC2.M16 和 DC2.M357，可预防 CHIKV 和 MAYV 诱导的小鼠肌肉骨骼疾病。这些发现增强了我们对人类甲病毒感染的交叉反应和交叉保护抗体反应的理解。
