Abstract
Although therapeutics targeting viral metabolic processes have been considered as promising strategies to treat herpesvirus infection, the metabolic requirements of gallid alphaherpesvirus 1 (ILTV), which is economically important to the poultry industry worldwide, remain largely unknown. Using the ILTV-susceptible but nonpermissive chicken cell line DF-1 and the ILTV-permissive chicken cell line LMH as models, the present study explored the metabolic requirements of ILTV by global transcriptome analysis and metabolome assays of ILTV infected cell lines in combination with a set of functional validations. The extensive metabolic exploration demonstrated that ILTV infection tended to promote a metabolic shift from glycolysis to fatty acid (FA) and nucleotide biosynthesis and utilizes glutamine independently of glutaminolysis, without significant general effect on the TCA cycle. In addition, different metabolic pathways were found to be required for distinct stages of ILTV replication. Glucose and glutamine were required for the transcription of viral immediate early gene ICP4 and subsequent steps of viral replication. However, FA synthesis was essential for assembly but not required for other upstream steps of ILTV replication. Moreover, the metabolic requirements of ILTV infection revealed in chicken cell lines were further validated in chicken primary cells isolated from chicken embryo kidneys and chicken embryo livers. The present study, to the best of our knowledge, provides the first global metabolic profile of animal herpesviruses and illustrates the main characteristics of the metabolic program of ILTV.
Highlights
The host cell metabolism provides viruses with all energy and macromolecules required for viral replication and thereby is a promising target for antiviral therapeutics
Both viruses are currently treated with drugs targeting nucleotide metabolism in the clinic, therapeu tic interventions at other points in the metabolic flux from glycolysis to fatty acid synthesis might prove more effective for the treatment of human cytomegalovirus (HCMV)
To study the susceptibility of DF-1 cells and leghorn male hepatoma (LMH) cells to ILTV, the fusion between the viral membrane and host cell membrane was detected by Fluorescence activated cell sorting (FACS) using virus preincubated with octadecyl rhodamine B chloride (R18), a lipophilic dye widely used for virus penetration detection
Summary
The host cell metabolism provides viruses with all energy and macromolecules required for viral replication and thereby is a promising target for antiviral therapeutics. HCMV increases the host glycolytic flux to feed the tricarboxylic acid (TCA) cycle for ultimate fatty acid (FA) synthesis; in contrast, HSV-1 mainly increases the anaplerotic influx to the TCA cycle through pyruvate carboxylase to feed pyrimidine biosynthesis [2]. Both viruses are currently treated with drugs targeting nucleotide metabolism in the clinic, therapeu tic interventions at other points in the metabolic flux from glycolysis to fatty acid synthesis might prove more effective for the treatment of HCMV. Extensive investigations of the metabolic requirements of more viruses are urgently needed to refine the rational design of virus-specific therapeutics
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