摘要
病毒感染是二十一世纪面临的主要医学挑战之一，从影响全球3％人口的丙肝病毒（HCV）流行病到最近爆发的西尼罗河病毒、寨卡病毒和埃博拉病毒感染。病毒缺乏进行自我复制所需的基础代谢机制。为了解决这个问题，它们劫持它们的宿主的代谢机制以便完成它们的生命周期和进行增殖。然而，科学家们仍然并没有很好地理解病毒与它们感染的有机体之间在代谢上的相互作用。这主要是因为人基因与代谢过程之间存在复杂的相互作用。
Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR. Pharmaceutical inhibition of HNF4α reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing virus-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPARα or FXR reversed HCV-induced ketogenesis but increased viral replication, demonstrating a novel host antiviral response. Our results show that virus-induced changes to a host's metabolism can be detrimental to its life cycle, thus revealing a biologically complex relationship between virus and host.
作者
Gahl Levy, Naomi Habib, Maria Angela Guzzardi, Daniel Kitsberg, David Bomze, Elishai Ezra, Merav Cohen, Nir Friedman
Yaakov Nahmias
Gahl Levy, Daniel Kitsberg, David Bomze, Merav Cohen, Nir Friedman
Yaakov Nahmias
Naomi Habib
Maria Angela Guzzardi
Elishai Ezra
Basak E Uygun
Korkut Uygun
Martin Trippler
Joerg F Schlaak
Oren Shibolet
Ella H Sklan
Joerg Timm
出处
《现代生物医学进展》
CAS
2016年第35期I0001-I0002,共2页
Progress in Modern Biomedicine
