Asparagine deprivation causes a reversible inhibition of Human Cytomegalovirus acute virus replication

Research output: Contribution to journalArticlepeer-review

Abstract

As obligate intracellular pathogens, viruses rely on the host cell machinery to replicate efficiently, with the host metabolism extensively manipulated for this purpose. High throughput siRNA screens provide a systematic approach for the identification of novel host virus interactions. Here, we report a large-scale screen for host factors important for human cytomegalovirus (HCMV), consisting of 6,881 siRNAs. We identified 47 proviral factors and 68 antiviral factors involved in a wide range of cellular processes including the mediator complex, proteasome function and mRNA splicing. Focused characterisation of one of the hits, asparagine synthetase (ASNS), demonstrated a strict requirement for asparagine for HCMV replication which leads to an early block in virus replication before the onset of DNA amplification. This effect is specific to HCMV, as knockdown of ASNS had little effect on herpes simplex virus-1 or influenza A virus replication, suggesting the restriction is not simply due to a failure in protein production. Remarkably, virus replication could be completely rescued seven days post-infection with addition of exogenous asparagine, indicating that while virus replication is restricted at an early stage, it maintains the capacity
for full replication days after initial infection. This study represents the most comprehensive siRNA screen for the identification of host factors involved in HCMV replication and identifies the non-essential amino acid, asparagine as a critical factor in regulating HCMV virus replication. These results have implications for control 31 of viral latency and the clinical treatment of HCMV in patients.
Original languageEnglish
Article numbere01651-19
JournalmBio
Volume10
Issue number5
Early online date8 Oct 2019
DOIs
Publication statusE-pub ahead of print - 8 Oct 2019

Keywords

  • asparagine
  • human cytomegalovirus
  • latency
  • antiviral
  • high throughput
  • siRNA screen
  • systems biology
  • virus

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