Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Victoria, Melbourne, Australia.
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, New South Wales, Sydney, Australia.
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.00286-18. Print 2018 Sep 15.
Human noroviruses are highly infectious single-stranded RNA (ssRNA) viruses and the major cause of nonbacterial gastroenteritis worldwide. With the discovery of murine norovirus (MNV) and the introduction of an effective model for norovirus infection and replication, knowledge about infection mechanisms and their impact on the host immune response has progressed. A major player in the immune response against viral infections is the group of major histocompatibility complex (MHC) class I proteins, which present viral antigen to immune cells. We have observed that MNV interferes with the antigen presentation pathway in infected cells by reducing the surface expression of MHC class I proteins. We have shown that MNV-infected dendritic cells or macrophages have lower levels of surface expression of MHC class I proteins than uninfected and bystander cells. Transcriptional analysis revealed that this defect is not due to a decreased amount of mRNA but is reflected at the protein level. We have determined that this defect is mediated via the MNV NS3 protein. Significantly, treatment of MNV-infected cells with the endocytic recycling inhibitor dynasore completely restored the surface expression of MHC class I proteins, whereas treatment with the proteasome inhibitor MG132 partly restored such expression. These observations indicate a role for endocytic recycling and proteasome-mediated degradation of these proteins. Importantly, we show that due to the reduced surface expression of MHC class I proteins, antigen presentation is inhibited, resulting in the inability of CD8 T cells to become activated in the presence of MNV-infected cells. Human noroviruses (HuNoVs) are the major cause of nonbacterial gastroenteritis worldwide and impose a great burden on patients and health systems every year. So far, no antiviral treatment or vaccine is available. We show that MNV evades the host immune response by reducing the amount of MHC class I proteins displayed on the cell surface. This reduction leads to a decrease in viral antigen presentation and interferes with the CD8 T cell response. CD8 T cells respond to foreign antigen by activating cytotoxic pathways and inducing immune memory to the infection. By evading this immune response, MNV is able to replicate efficiently in the host, and the ability of cells to respond to consecutive infections is impaired. These findings have a major impact on our understanding of the ways in which noroviruses interact with the host immune response and manipulate immune memory.
人类诺如病毒是高度传染性的单链 RNA（ssRNA）病毒，是全球非细菌性胃肠炎的主要病因。随着鼠诺如病毒（MNV）的发现和有效的诺如病毒感染和复制模型的引入，人们对感染机制及其对宿主免疫反应的影响有了更多的了解。在抗病毒感染的免疫反应中，主要参与者是主要组织相容性复合体（MHC）I 类蛋白，它将病毒抗原呈递给免疫细胞。我们观察到 MNV 通过降低 MHC I 类蛋白的表面表达来干扰感染细胞中的抗原呈递途径。我们已经表明，与未感染和旁观者细胞相比，MNV 感染的树突状细胞或巨噬细胞表面 MHC I 类蛋白的表达水平较低。转录分析显示，这种缺陷不是由于 mRNA 量减少引起的，而是反映在蛋白质水平上。我们已经确定，这种缺陷是通过 MNV NS3 蛋白介导的。重要的是，用内吞体再循环抑制剂 dynasore 处理 MNV 感染的细胞可完全恢复 MHC I 类蛋白的表面表达，而用蛋白酶体抑制剂 MG132 处理则部分恢复了这种表达。这些观察结果表明内吞体再循环和蛋白酶体介导的这些蛋白降解起作用。重要的是，我们表明，由于 MHC I 类蛋白的表面表达减少，抗原呈递受到抑制，导致在存在 MNV 感染的细胞的情况下，CD8 T 细胞无法被激活。人类诺如病毒（HuNoVs）是全球非细菌性胃肠炎的主要病因，每年给患者和卫生系统带来巨大负担。迄今为止，尚无抗病毒治疗或疫苗。我们表明，MNV 通过降低细胞表面显示的 MHC I 类蛋白的数量来逃避宿主的免疫反应。这种减少导致病毒抗原呈递减少，并干扰 CD8 T 细胞反应。CD8 T 细胞通过激活细胞毒性途径并诱导对感染的免疫记忆来对外国抗原作出反应。通过逃避这种免疫反应，MNV 能够在宿主中有效地复制，并且细胞对连续感染的反应能力受损。这些发现对我们理解诺如病毒与宿主免疫反应相互作用和操纵免疫记忆的方式具有重大影响。
