Abstract
Enterovirus 71 (EV71) infection is an endemic disease in Southeast Asia and China. We have previously shown that EV71 virus causes functional changes in mitochondria. It is speculative whether EV71 virus alters the host cell metabolism to its own benefit. Using a metabolomics approach, we demonstrate that EV71-infected Vero cells had significant changes in metabolism. Glutathione and its related metabolites, and several amino acids, such as glutamate and aspartate, changed significantly with the infectious dose of virus. Other pathways, including glycolysis and tricarboxylic acid cycle, were also altered. A change in glutamine/glutamate metabolism is critical to the viral infection. The presence of glutamine in culture medium was associated with an increase in viral replication. Dimethyl α-ketoglutarate treatment partially mimicked the effect of glutamine supplementation. In addition, the immunoblot analysis revealed that the expression of glutamate dehydrogenase (GDH) and trifunctional carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) increased during infection. Knockdown of expression of glutaminase (GLS), GDH and CAD drastically reduced the cytopathic effect (CPE) and viral replication. Furthermore, we found that CAD bound VP1 to promote the de novo pyrimidine synthesis. Our findings suggest that virus may induce metabolic reprogramming of host cells to promote its replication through interactions between viral and host cell proteins.
Highlights
IntroductionThe virion consists of an icosahedral capsid enclosing a single positive-strand genomic RNA molecule
Enteroviruses are a group of RNA viruses belonging to the family Picornaviridae [1]
To study the metabolic changes associated with Enterovirus 71 (EV71) infection, we infected Vero cells with EV71 at extracts were analyzed by Ultra Performance Liquid Chromatography (UPLC)-Q-TOF-MS operated in electrospray ionization (ESI) positive and an multiplicity of infection (MOI) of 0, 0.3125, 0.625, or 1.25, and extracted their metabolites for metabolomic analysis
Summary
The virion consists of an icosahedral capsid enclosing a single positive-strand genomic RNA molecule. HFMD is usually self-limiting and is characterized by a mild fever and the presence of oral cavity ulcers, herpangina and papulovesicular rash on extremities. Few patients develop such neurological complications as aseptic meningitis, encephalitis, and acute flaccid paralysis, and cardiopulmonary manifestations. EV71 infection has been endemic in Asia–Pacific regions, including China, Taiwan, Hong Kong, Malaysia, Singapore, Japan, and Korea [2,3,4]. The largest outbreak has occurred in China, with about 3 million cases and 1500 deaths being reported [5,6]
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