Norovirus alters host metabolism for efficient virus replication

Adam Hafner, University of Michigan

Adam Hafner1, Harrison Wong2, Li Zhang2, Austin Wright3, Mia Alfajaro4, Costas Lyssiotis2, Timothy J. Nice3, Craig Wilen4, Christiane E. Wobus1 1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA 2Department of Cancer Biology, University of Michigan Medical School, Ann Arbor, MI, USA 3Department of Molecular Microbiology and Immunology, Oregon State University School of Medicine, Corvallis, OR, USA 4Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

Entry and Replication

Human noroviruses (HNoVs) are single-stranded, positive-sense RNA viruses that are the leading cause of acute non-bacterial gastroenteritis worldwide. Despite the devastating public health impact of HNoV infections, neither vaccines nor therapeutics exist, underscoring the need for further investigations to better understand NoV biology. Viruses hijack host metabolic pathways, creating more favorable intracellular environments to ensure optimal reproduction. However, little is known about the ability of NoVs to reprogram host metabolism. Our published metabolomic and quantitative flux analysis revealed that murine norovirus 1 (MNV-1) upregulates and relies on glycolysis and glutaminolysis for efficient virus infection. Mechanistic investigations demonstrate that the activity of glutaminase, the rate-limiting enzyme in the glutamine catabolic pathway, is upregulated during MNV infections and these changes are mediated via the non-structural protein NS1/2. Importantly, studies in intestinal epithelial cells revealed that MNV upregulates central carbon metabolism in CD300lf-expressing murine intestinal enteroids (MIEs) and in murine tuft cell cultures. Similar to infected macrophages, MNV's efficient reproduction in MIEs depended on both glycolysis and glutaminolysis. Extension of metabolic investigations to HNoV, revealed its efficient replication in human intestinal enteroids (HIEs) also required both glycolysis and glutaminolysis. Early mechanistic investigations indicated that HNoV NS1/2 also increases glutaminase enzymatic activity. Current studies aim to determine the full range of metabolic alterations in HNoV-infected intestinal epithelial cells and uncover the underlying mechanisms. Collectively, these data demonstrate the importance of multiple host metabolic pathways for productive NoV infection and the ability of a noroviral protein to alter the activity of a metabolic enzyme.