Metabolic Reprogramming of Host Cells in Response to Enteroviral Infection

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.

Cytosine drives evolution of SARS‐CoV‐2

“…It was also observed early on that an increase in cytoplasmic CTP accelerated the rate of phospholipids synthesis in poliomyelitis‐infected cells (Choy et al ., ). Yet another most significant feature of CAD, relevant to our hypotheses, is that its activity is modulated by a dedicated viral protein during enteroviral infection (Cheng et al ., ). This should prompt further analysis of pyrimidine metabolism in relation with SARS‐CoV‐2 infection, in particular looking for virus‐encoded functions involved in interference with cytosine metabolism, as we now document.…”

SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

“…For instance, in absence of exogenous glutamine, vaccinia virus (VACV)-infected cells exhibited a significant decline in viral particle production while depriving infected cells of exogenous glucose had no considerable alternation in virus generation (Fontaine et al, 2014 ). Likewise, enterovirus 71 (EV71) exhibited similar results in replication corresponds to a change in glutamine/glutamate metabolism (Cheng et al, 2020 ). However, HCMV demonstrated an excessive dependence on the utilization of both glucose and glutamine for virus replication in infected-cells (Munger et al, 2006 , 2008 ; Chambers et al, 2010 ; Sanchez et al, 2015 ).…”

Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology

“…In order for a virus to efficiently replicate, it must hijack the host cell's mechanism for obtaining macromolecules including amino acids and nucleotides 79,80 . Previously, several viruses have been identified to induce host cell metabolic reprogramming to satisfy the biosynthetic and energy requirements needed for replication [81][82][83][84] . To identify metabolic features of cells able to be infected by SARS-CoV-2, metabolites associated with ACE2 expression were investigated.…”