Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication

Area of Science:

• Virology
• Cellular Metabolism
• Host-Pathogen Interactions

Background:

• Viruses are obligate intracellular parasites dependent on host cell metabolism.
• Understanding virus-induced metabolic alterations is crucial for controlling viral infections.
• Noroviruses (NoVs) are significant causes of viral gastroenteritis.

Purpose of the Study:

• To investigate host cell metabolic requirements for murine norovirus (MNV) infection.
• To elucidate the mechanisms by which NoVs alter host metabolism.
• To identify viral factors involved in metabolic reprogramming.

Main Methods:

• Comparative analysis of three MNV strains (MNV-1, CR3, CR6) in macrophages.
• Metabolic flux analysis of NoV-infected cells.
• Glutamine deprivation experiments to assess viral lifecycle impact.
• Enzyme activity assays for glutaminase.

Main Results:

• All MNV strains required glycolysis, glutaminolysis, and the pentose phosphate pathway.
• MNV-1 uniquely depended on oxidative phosphorylation.
• Metabolic flux analysis showed upregulated glycolysis and glutaminolysis during MNV-1 infection.
• Glutamine deprivation impaired viral genome replication, protein synthesis, assembly, and egress.
• MNV infection and NS1/2 protein increased glutaminase activity.

Conclusions:

• The study provides the first investigation into NoV-induced alterations of host glutaminolysis.
• Viral protein NS1/2 is identified as a regulator of glutaminolysis in RNA viruses.
• Findings enhance understanding of virus-host metabolic interactions and suggest potential avenues for human NoV cultivation.