Baldridge Megan T, Lee Sanghyun, Brown Judy J, McAllister Nicole, Urbanek Kelly, Dermody Terence S, Nice Timothy J, Virgin Herbert W
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
J Virol. 2017 Mar 13;91(7). doi: 10.1128/JVI.02079-16. Print 2017 Apr 1.
Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in -deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC expression with reovirus. These mice phenocopied -null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection Upon murine norovirus or reovirus infection, depletion in IECs largely recapitulated the phenotype seen in mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections.
λ干扰素（IFN-λ）在预防和治疗感染方面，对包括诺如病毒和轮状病毒在内的多种肠道病毒病原体具有强大的抗病毒作用。然而，由于肠道包含多种不同类型的细胞，IFN-λ发挥其抗病毒作用所作用的细胞尚不清楚。在此，我们试图通过构建IFN-λ受体谱系特异性缺失的小鼠来鉴定IFN-λ反应性细胞。我们发现，小肠和结肠的肠道上皮细胞（IECs）上IFNLR1的表达是肠道IFN-λ抗病毒活性所必需的。IECs的表达还决定了IFN-λ在解决持续性小鼠诺如病毒（MNoV）感染中的功效，并调节组织中的粪便排毒和病毒滴度。因此，IECs的表达对于对内源性和外源性IFN-λ的反应都是必需的。我们通过在IFNLR1缺陷小鼠中扩展这些发现，进一步证明了IECs的表达是IFN-λ杀菌性先天免疫作用所必需的。最后，我们通过用呼肠孤病毒感染特异性缺乏IECs表达的小鼠，评估我们的发现是否适用于多种病毒病原体。这些小鼠表现出与IFNLR1基因敲除动物相似的表型，肠道组织滴度增加，呼肠孤病毒粪便排毒增强。因此，IECs是对IFN-λ作出反应以控制多种肠道病毒的关键细胞类型。这是首个支持IECs在IFN-λ介导的肠道病毒感染控制中起重要作用的遗传学证据，这些发现为IFN-λ介导抗病毒活性的机制提供了见解。人类诺如病毒（HNoVs）是全球流行性肠胃炎的主要病因。III型干扰素（IFN-λ）可控制肠道中的肠道病毒感染，并已被证明可治愈小鼠诺如病毒，这是HNoVs的一种小动物模型。使用条件性基因敲除小鼠的遗传学方法，我们确定IECs是控制肠道病毒感染中主要的IFN-λ反应性细胞。在小鼠感染诺如病毒或呼肠孤病毒后，IECs的缺失在很大程度上重现了IFNLR1基因敲除小鼠中观察到的表型，即肠道组织病毒滴度更高，粪便中病毒排毒增加。此外，IFN-λ介导的针对小鼠诺如病毒的杀菌免疫需要IECs对IFN-λ作出反应的能力。这些发现阐明了这种细胞因子的作用机制，并强调了IFN-λ在治疗黏膜病毒感染方面的治疗潜力。
