Miles Linde A, Burga Laura N, Gardner Eric E, Bostina Mihnea, Poirier John T, Rudin Charles M
Molecular Pharmacology Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Microbiology and Immunology and.
J Clin Invest. 2017 Aug 1;127(8):2957-2967. doi: 10.1172/JCI93472. Epub 2017 Jun 26.
Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. It has shown promise as a cancer therapeutic in preclinical studies and early-phase clinical trials. Here, we have identified anthrax toxin receptor 1 (ANTXR1) as the receptor for SVV using genome-wide loss-of-function screens. ANTXR1 is necessary for permissivity in vitro and in vivo. However, robust SVV replication requires an additional innate immune defect. We found that SVV interacts directly and specifically with ANTXR1, that this interaction is required for SVV binding to permissive cells, and that ANTXR1 expression is necessary and sufficient for infection in cell lines with decreased expression of antiviral IFN genes at baseline. Finally, we identified the region of the SVV capsid that is responsible for receptor recognition using cryoelectron microscopy of the SVV-ANTXR1-Fc complex. These studies identify ANTXR1, a class of receptor that is shared by a mammalian virus and a bacterial toxin, as the cellular receptor for SVV.
塞内卡山谷病毒（SVV）是一种对神经内分泌癌具有选择性嗜性的溶瘤微小核糖核酸病毒。在临床前研究和早期临床试验中，它已显示出作为癌症治疗药物的潜力。在此，我们通过全基因组功能丧失筛选确定炭疽毒素受体1（ANTXR1）为SVV的受体。ANTXR1在体外和体内的易感性中是必需的。然而，强大的SVV复制需要额外的先天免疫缺陷。我们发现SVV与ANTXR1直接且特异性地相互作用，这种相互作用是SVV与允许性细胞结合所必需的，并且在基线时抗病毒IFN基因表达降低的细胞系中，ANTXR1的表达对于感染是必要且充分的。最后，我们使用SVV-ANTXR1-Fc复合物的冷冻电子显微镜确定了SVV衣壳中负责受体识别的区域。这些研究确定ANTXR1，一种哺乳动物病毒和细菌毒素共有的受体类别，为SVV的细胞受体。
