PDCoV S mAb

Porcine deltacoronavirus (PDCoV) is an emerging enteric pathogen in pigs that has recently been detected in humans. Despite this zoonotic concern, the antigenic structure of PDCoV remains unknown. The virus relies on its spike (S) protein for cell entry, making it a prime target for neutralizing antibodies. Here we generated and characterized a set of neutralizing antibodies targeting the S protein, shedding light on PDCoV S interdomain crosstalk and its vulnerable sites. Among the four identified antibodies, one targets the S1A domain, causing local and long-range conformational changes, resulting in partial exposure of the S1B domain. The other antibodies bind the S1B domain, disrupting binding to the APN receptor. Notably, the epitopes of these S1B-targeting antibodies are concealed in the prefusion S trimer conformation, highlighting the necessity for conformational changes for effective antibody binding. The binding footprint of one S1B binder entirely overlaps with APN-interacting residues and thus targets a highly conserved epitope. These findings provide critical structural insights into the humoral immune response against the PDCoV S protein, potentially guiding vaccine and therapeutic development for this zoonotic pathogen.

猪德尔塔冠状病毒（Porcine deltacoronavirus, PDCoV）是一种新近在猪群中发现的肠道致病性病原，近期亦在人类样本中被检出。尽管存在此类人畜共患公共卫生隐患，PDCoV的抗原结构至今仍未明确。该病毒依赖其刺突（S）蛋白完成细胞入侵，因此刺突蛋白是中和抗体的核心作用靶点。本研究制备并表征了一系列靶向S蛋白的中和抗体，为解析PDCoV S蛋白的结构域间串扰机制及其易感位点提供了新视角。在鉴定得到的4株抗体中，1株靶向S1A结构域，可引发局部及远程构象变化，进而部分暴露S1B结构域；其余抗体结合S1B结构域，通过干扰病毒与氨肽酶N（APN）受体的结合发挥中和作用。值得注意的是，这些靶向S1B结构域的抗体其识别表位在预融合状态的S三聚体构象中处于隐蔽状态，这提示有效的抗体结合需要病毒先发生构象改变。其中1株S1B结合型抗体的结合足迹完全覆盖了APN受体结合位点，因此其靶向的表位具有高度保守性。本研究结果为抗PDCoV S蛋白的体液免疫应答机制提供了关键结构生物学见解，有望为该人畜共患病原的疫苗研发与治疗策略开发提供重要指导。