Division of Animal Science, College of Agriculture Food and Natural Resources, University of Missouri, Columbia, Columbia, MO, 65211, USA.
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA.
Sci Rep. 2022 Mar 23;12(1):5009. doi: 10.1038/s41598-022-09123-x.
Senecavirus A (SVA) is a cause of vesicular disease in pigs, and infection rates are rising within the swine industry. Recently, anthrax toxin receptor 1 (ANTXR1) was revealed as the receptor for SVA in human cells. Herein, the role of ANTXR1 as a receptor for SVA in pigs was investigated by CRISPR/Cas9 genome editing. Strikingly, ANTXR1 knockout (KO) pigs exhibited features consistent with the rare disease, GAPO syndrome, in humans. Fibroblasts from wild type (WT) pigs supported replication of SVA; whereas, fibroblasts from KO pigs were resistant to infection. During an SVA challenge, clinical symptoms, including vesicular lesions, and circulating viremia were present in infected WT pigs but were absent in KO pigs. Additional ANTXR1-edited piglets were generated that were homozygous for an in-frame (IF) mutation. While IF pigs presented a GAPO phenotype similar to the KO pigs, fibroblasts showed mild infection, and circulating SVA nucleic acid was decreased in IF compared to WT pigs. Thus, this new ANTXR1 mutation resulted in decreased permissiveness of SVA in pigs. Overall, genetic disruption of ANTXR1 in pigs provides a unique model for GAPO syndrome and prevents circulating SVA infection and clinical symptoms, confirming that ANTXR1 acts as a receptor for the virus.
塞内卡病毒 A（SVA）是一种引起猪水疱病的病原体，其在猪群中的感染率正在上升。最近，炭疽毒素受体 1（ANTXR1）被揭示为人类细胞中 SVA 的受体。在此，通过 CRISPR/Cas9 基因组编辑研究了 ANTXR1 在猪中作为 SVA 受体的作用。引人注目的是，ANTXR1 敲除（KO）猪表现出与人类罕见疾病 GAPO 综合征一致的特征。野生型（WT）猪的成纤维细胞支持 SVA 的复制；而 KO 猪的成纤维细胞则对感染具有抗性。在 SVA 攻毒期间，受感染的 WT 猪出现了临床症状，包括水疱病变和循环病毒血症，但 KO 猪则没有。还产生了具有框内（IF）突变的额外 ANTXR1 编辑仔猪。虽然 IF 猪表现出与 KO 猪相似的 GAPO 表型，但成纤维细胞显示出轻度感染，并且与 WT 猪相比，IF 猪的循环 SVA 核酸减少。因此，这种新的 ANTXR1 突变导致 SVA 在猪中的易感性降低。总体而言，猪中 ANTXR1 的遗传破坏为 GAPO 综合征提供了一个独特的模型，并防止了循环 SVA 感染和临床症状，证实了 ANTXR1 是病毒的受体。
