RT Journal Article
SR Electronic
T1 Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.30.526357
DO 10.1101/2023.01.30.526357
A1 Sarah A. Clark
A1 Angie Vazquez
A1 Kelsey Furiya
A1 Madeleine K. Splattstoesser
A1 Abdullah K. Bashmail
A1 Haleigh Schwartz
A1 Makaiya Russell
A1 Shun-Je Bhark
A1 Osvaldo K. Moreno
A1 Morgan McGovern
A1 Eric R. Owsley
A1 Timothy A. Nelson
A1 Erica Sanchez
A1 Tracie Delgado
YR 2023
UL http://biorxiv.org/content/early/2023/01/31/2023.01.30.526357.abstract
AB Oncogenic virus infections are estimated to cause ∼15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein Barr Virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors.IMPORTANCE Viruses are intracellular parasites which lack their own metabolism, so they must hijack host cell metabolic machinery in order to increase the production of energy, proteins, fats, and genetic material necessary to replicate. Using murine herpesvirus 68 (MHV-68) as a model system to understand how similar human gammaherpesviruses cause cancer, we profiled the metabolic changes that occur during lytic MHV-68 infection and replication. We found MHV-68 infection of host cells increases glucose, glutamine, lipid, and nucleotide metabolic pathways. We also showed inhibition or starvation of glucose, glutamine or lipid metabolic pathways results in an inhibition of virus production. Ultimately, targeting changes in host cell metabolism due to viral infection can be used to treat gammaherpesvirus induced cancers and infections in humans.Competing Interest StatementThe authors have declared no competing interest.