The recent approval of oncolytic virus for therapy of melanoma patients has increased the need for precise evaluation of the mechanisms by which oncolytic viruses affect tumor growth. Here we show that the human NK cell-activating receptor NKp46 and the orthologous mouse protein NCR1 recognize the reovirus sigma1 protein in a sialic-acid-dependent manner. We identify sites of NKp46/NCR1 binding to sigma1 and show that sigma1 binding by NKp46/NCR1 leads to NK cell activation in vitro. Finally, we demonstrate that NCR1 activation is essential for reovirus-based therapy in vivo. Collectively, we have identified sigma1 as a novel ligand for NKp46/NCR1 and demonstrated that NKp46/NCR1 is needed both for clearance of reovirus infection and for reovirus-based tumor therapy.

IMPORTANCE Reovirus infects much of the population during childhood, causing mild disease, and hence is considered to be efficiently controlled by the immune system. Reovirus also specifically infects tumor cells, leading to tumor death, and is currently being tested in human clinical trials for cancer therapy. The mechanisms by which our immune system controls reovirus infection and tumor killing are not well understood. We report here that natural killer (NK) cells recognize a viral protein named sigma1 through the NK cell-activating receptor NKp46. Using several mouse tumor models, we demonstrate the importance of NK cells in protection from reovirus infection and in reovirus killing of tumors in vivo. Collectively, we identify a new ligand for the NKp46 receptor and provide evidence for the importance of NKp46 in the control of reovirus infections and in reovirus-based cancer therapy.

溶瘤病毒用于治疗黑素瘤患者的最新批准增加了对溶瘤病毒影响肿瘤生长的机制进行精确评估的需求。在这里，我们显示人NK细胞激活受体NKp46和直系同源小鼠蛋白NCR1以唾液酸依赖性方式识别呼肠孤病毒sigma1蛋白。我们确定NKp46 / NCR1结合sigma1的网站，并表明NKp46 / NCR1结合sigma1导致体外NK细胞活化。最后，我们证明了NCR1激活对于基于呼肠孤病毒的体内治疗至关重要。总的来说，我们已经确定sigma1是NKp46 / NCR1的新型配体，并证明NKp46 / NCR1既需要清除呼肠孤病毒感染，又需要基于呼肠孤病毒的肿瘤治疗。

重要事项呼肠孤病毒在童年时期感染了大部分人群，导致了轻度疾病，因此被认为可以通过免疫系统有效控制。呼肠孤病毒还特异性感染肿瘤细胞，导致肿瘤死亡，目前正在人类临床试验中进行癌症治疗的测试。我们的免疫系统控制呼肠孤病毒感染和杀死肿瘤的机制尚不清楚。我们在这里报告自然杀手（NK）细胞通过NK细胞激活受体NKp46识别名为sigma1的病毒蛋白。使用几种小鼠肿瘤模型，我们证明了NK细胞在预防呼肠孤病毒感染和体内呼肠孤病毒杀死中的重要性。总的来说，我们确定了NKp46受体的新配体，并提供了NKp46在控制呼肠孤病毒感染和基于呼肠孤病毒的癌症治疗中的重要性的证据。