什麼是諾如病毒最優複製的內在因素？

近日，美國密歇根大學微生物和免疫學系Christiane E. Wobus課題組在美國微生物協會旗下的Host-Microbe Biology雜誌上發表如下圖的論文。該研究揭示了糖酵解是一種諾如病毒複製的毒力決定因素，提供了治療諾如病毒感染的新靶點。

中心碳代謝的代謝途徑——糖酵解和氧化磷酸化(OXPHOS)，是決定病毒感染後果的重要宿主因子，並可被某些病毒所操縱以利於感染。然而，代謝調節的機制及其對病毒複製的影響差別很大。

本研究中，研究者介紹了諾如病毒感染細胞的第一個代謝組學和能量譜，揭示了在小鼠諾如病毒(MNV)感染過程中糖酵解、OXPHOS和戊糖磷酸途徑(PPP)的增加。抑制巨噬細胞中2-脫氧葡萄糖(2DG)的糖酵解是MNV最佳感染的重要因素，而抑制PPP和OXPHOS對MNV感染的影響相對較小。2DG在病毒攝取和衣殼脫殼後影響病毒生命周期的早期階段，導致病毒蛋白產量和病毒RNA的減少。對於MNV感染，糖酵解的要求是特異的，不依賴於I型干擾素的抗病毒反應，且不太可能是由於宿主細胞核苷酸合成的缺乏。MNV感染增加了細胞代謝的主要調節因子蛋白激酶Akt的激活，而不是AMP激活的蛋白激酶(AMPK)的激活，提示在諾如病毒感染過程中Akt信號通路上調了宿主代謝。

總之，研究表明靶細胞的代謝狀態是決定諾如病毒複製程度的內在宿主因素，並暗示糖酵解是一種毒力決定因素。結果進一步表明，細胞代謝是諾如病毒感染的一種新的治療靶點，也是目前人類諾如病毒培養系統的改進。

DOI:10.1128/mBio.02175-18

ABSTRACTThe metabolic pathways of central carbon metabolism, glycolysis and oxidative phosphorylation (OXPHOS), are important host factors that determine the outcome of viral infections and can be manipulated by some viruses to favor infection. However, mechanisms of metabolic modulation and their effects on viral replication vary widely. Herein, we present the first metabolomics and energetic profiling of norovirus-infected cells, which revealed increases in glycolysis, OXPHOS, and the pentose phosphate pathway (PPP) during murine norovirus (MNV) infection. Inhibiting glycolysis with 2-deoxyglucose (2DG) in macrophages revealed that glycolysis is an important factor for optimal MNV infection, while inhibiting the PPP and OXPHOS showed a relatively minor impact of these pathways on MNV infection. 2DG affected an early stage in the viral life cycle after viral uptake and capsid uncoating, leading to decreased viral protein production and viral RNA. The requirement of glycolysis was specific for MNV (but not astrovirus) infection, independent of the type I interferon antiviral response, and unlikely to be due to a lack of host cell nucleotide synthesis. MNV infection increased activation of the protein kinase Akt, but not AMP-activated protein kinase (AMPK), two master regulators of cellular metabolism, implicating Akt signaling in upregulating host metabolism during norovirus infection. In conclusion, our findings suggest that the metabolic state of target cells is an intrinsic host factor that determines the extent of norovirus replication and implicates glycolysis as a virulence determinant. They further point to cellular metabolism as a novel therapeutic target for norovirus infections and improvements in current human norovirus culture systems.

IMPORTANCEViruses depend on the host cells they infect to provide the machinery and substrates for replication. Host cells are highly dynamic systems that can alter their intracellular environment and metabolic behavior, which may be helpful or inhibitory for an infecting virus. In this study, we show that macrophages, a target cell of murine norovirus (MNV), increase glycolysis upon viral infection, which is important for early steps in MNV infection. Human noroviruses (hNoV) are a major cause of gastroenteritis globally, causing enormous morbidity and economic burden. Currently,no effective antivirals or vaccines exist for hNoV, mainly due to the lack of high-efficiencyin vitroculture models for their study. Thus, insights gained from the MNV model may reveal aspects of host cell metabolism that can be targeted for improving hNoV cell culture systems and for developing effective antiviral therapies.

本期編輯：烏龜

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