Cellular tropism during persistent viral infection is commonly conferred by the interaction of a viral surface protein with a host receptor complex. Norovirus, the leading global cause of gastroenteritis, can be persistently shed during infection, but its in vivo cellular tropism and tropism determinants remain unidentified. Using murine norovirus (MNoV), we determine that a small number of intestinal epithelial cells (IECs) serve as the reservoir for fecal shedding and persistence. The viral non-structural protein NS1, rather than a viral surface protein, determines IEC tropism. Expression of NS1 from a persistent MNoV strain is sufficient for an acute MNoV strain to target IECs and persist. In addition, interferon-lambda (IFN-λ) is a key host determinant blocking MNoV infection in IECs. The inability of acute MNoV to shed and persist is rescued in Ifnlr1^−/− mice, suggesting that NS1 evades IFN-λ-mediated antiviral immunity. Thus, NS1 and IFN-λ interactions govern IEC tropism and persistence of MNoV.

持续性病毒感染期间的细胞向性通常是由病毒表面蛋白与宿主受体复合物的相互作用赋予的。诺如病毒是全球胃肠炎的主要原因，在感染过程中可以持续脱落，但其体内细胞向性和向性决定因素仍不清楚。使用鼠诺如病毒（MNoV），我们确定少量肠上皮细胞（IEC）充当粪便脱落和持久性的储存库。决定 IEC 趋向性的是病毒非结构蛋白 NS1，而不是病毒表面蛋白。持久性 MNoV 毒株中 NS1 的表达足以让急性 MNoV 毒株靶向 IEC 并持续存在。此外，干扰素-λ (IFN-λ) 是阻止 IEC 中 MNoV 感染的关键宿主决定因素。急性 MNoV 无法脱落和持续存在的现象在Ifnlr1 ^−/−小鼠中得以恢复，这表明 NS1 逃避了 IFN-λ 介导的抗病毒免疫。因此，NS1 和 IFN-λ 的相互作用控制着 IEC 向性和 MNoV 的持续性。