Murine Norovirus Infection Results in Anti-inflammatory Response Downstream of Amino Acid Depletion in Macrophages.
Murine Norovirus Infection Results in Anti-inflammatory Response Downstream of Amino Acid Depletion in Macrophages.
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DOI：
10.1128/jvi.01134-21
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发表时间：
2021-09-27
影响因子：
5.4
通讯作者：
Locker N
中科院分区：
文献类型：
--
作者：
Brocard M;Lu J;Hall B;Borah K;Moller-Levet C;Georgana I;Sorgeloos F;Beste DJV;Goodfellow IG;Locker N
小鼠诺如病毒（MNV）感染导致较晚的翻译关闭，这被认为是导致体外和体内观察到的先天免疫反应减弱和延迟的原因。最近，我们进一步证明了MNV感染期间真核起始因子2 （eIF2α）激酶GCN2的α亚基活化，这与代谢应激期间的免疫调节和对炎症信号的抵抗有关。虽然病毒感染通常与双链RNA （dsRNA）结合模式识别受体PKR的激活有关，但我们假设在感染细胞中建立代谢应激是一个前病毒事件，被MNV利用，通过削弱先天免疫反应的激活来促进复制。在这项研究中，我们使用多组学方法来表征MNV复制过程中的细胞反应。我们证明了与综合应激反应相关的途径的激活，这是巨噬细胞抗炎表型的已知驱动因素。特别是，MNV感染引起与GCN2和ATF2信号相关的氨基酸失衡。重要的是，这种重编程缺乏典型先天免疫反应的特征，ATF/CHOP靶点GDF15导致缺乏抗病毒反应。我们认为mnv诱导的代谢应激支持宿主对病毒复制和繁殖的耐受性的建立。在病毒感染期间，宿主防御的典型特征是分泌促炎自分泌和旁分泌细胞因子，增强干扰素（IFN）反应，并通过激活JAK和Stat信号传导诱导抗病毒反应。为了避免这些并繁殖，病毒进化出了逃避或抵消宿主感知的策略。在这项研究中，我们证明了小鼠诺如病毒通过激活代谢应激反应来控制抗病毒反应，代谢应激反应激活氨基酸反应并损害炎症信号。这突出了病毒对策武器库中的新工具，并证明了目前知之甚少的病毒感染期间发生的代谢重编程的重要性。
Murine norovirus (MNV) infection results in a late translation shutoff that is proposed to contribute to the attenuated and delayed innate immune response observed both in vitro and in vivo. Recently, we further demonstrated the activation of the α subunit of eukaryotic initiation factor 2 (eIF2α) kinase GCN2 during MNV infection, which has been previously linked to immunomodulation and resistance to inflammatory signaling during metabolic stress. While viral infection is usually associated with activation of double-stranded RNA (dsRNA) binding pattern recognition receptor PKR, we hypothesized that the establishment of a metabolic stress in infected cells is a proviral event, exploited by MNV to promote replication through weakening the activation of the innate immune response. In this study, we used multi-omics approaches to characterize cellular responses during MNV replication. We demonstrate the activation of pathways related to the integrated stress response, a known driver of anti-inflammatory phenotypes in macrophages. In particular, MNV infection causes an amino acid imbalance that is associated with GCN2 and ATF2 signaling. Importantly, this reprogramming lacks the features of a typical innate immune response, with the ATF/CHOP target GDF15 contributing to the lack of antiviral responses. We propose that MNV-induced metabolic stress supports the establishment of host tolerance to viral replication and propagation. IMPORTANCE During viral infection, host defenses are typically characterized by the secretion of proinflammatory autocrine and paracrine cytokines, potentiation of the interferon (IFN) response, and induction of the antiviral response via activation of JAK and Stat signaling. To avoid these and propagate, viruses have evolved strategies to evade or counteract host sensing. In this study, we demonstrate that murine norovirus controls the antiviral response by activating a metabolic stress response that activates the amino acid response and impairs inflammatory signaling. This highlights novel tools in the viral countermeasures arsenal and demonstrates the importance of the currently poorly understood metabolic reprogramming occurring during viral infections.