title: Cross Talk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication.
abstract: Viruses are solely dependent on host cells to propagate; therefore, understanding virus-host interaction is important for antiviral drug development. Since de novo nucleotide biosynthesis is essentially required for both host cell metabolism and viral replication, specific catalytic enzymes of these pathways have been explored as potential antiviral targets. In this study, we investigated the role of different enzymatic cascades of nucleotide biosynthesis in hepatitis E virus (HEV) replication. By profiling various pharmacological inhibitors of nucleotide biosynthesis, we found that targeting the early steps of the purine biosynthesis pathway led to the enhancement of HEV replication, whereas targeting the later step resulted in potent antiviral activity via the depletion of purine nucleotide. Furthermore, the inhibition of the pyrimidine pathway resulted in potent anti-HEV activity. Interestingly, all of these inhibitors with anti-HEV activity concurrently triggered the induction of antiviral interferon-stimulated genes (ISGs). Although ISGs are commonly induced by interferons via the JAK-STAT pathway, their induction by nucleotide synthesis inhibitors is completely independent of this classical mechanism. In conclusion, this study revealed an unconventional novel mechanism of cross talk between nucleotide biosynthesis pathways and cellular antiviral immunity in constraining HEV infection. Targeting particular enzymes in nucleotide biosynthesis represents a viable option for antiviral drug development against HEV. HEV is the most common cause of acute viral hepatitis worldwide and is also associated with chronic hepatitis, especially in immunocompromised patients. Although often an acute and self-limiting infection in the general population, HEV can cause severe morbidity and mortality in certain patients, a problem compounded by the lack of FDA-approved anti-HEV medication available. In this study, we have investigated the role of the nucleotide synthesis pathway in HEV infection and its potential for antiviral drug development. We show that targeting the later but not the early steps of the purine synthesis pathway exerts strong anti-HEV activity. In particular, IMP dehydrogenase (IMPDH) is the most important anti-HEV target of this cascade. Importantly, the clinically used IMPDH inhibitors, including mycophenolic acid and ribavirin, have potent anti-HEV activity. Furthermore, targeting the pyrimidine synthesis pathway also exerts potent antiviral activity against HEV. Interestingly, antiviral effects of nucleotide synthesis pathway inhibitors appear to depend on the medication-induced transcription of antiviral interferon-stimulated genes. Thus, this study reveals an unconventional novel mechanism as to how nucleotide synthesis pathway inhibitors can counteract HEV replication.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Shokrollahi
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Anesthesiology, Laboratory of Experimental Anesthesiology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Nicolaas J H
authors.initials: NJ
authors.lastname: Raat
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D006151:Guanosine / Q000494:pharmacology; D016752:Hepatitis E virus / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007111:Immunity, Cellular / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000494:pharmacology; D009711:Nucleotides / Q000378:metabolism*; D012254:Ribavirin / Q000494:pharmacology; D014529:Uridine / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009711:Nucleotides; D006151:Guanosine; D012254:Ribavirin; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D014529:Uridine