In Vitro Hepatitis C Virus Infection and Hepatic Choline Metabolism
by
Kaelan Gobeil Odai 1,2,†, Conor O’Dwyer 1,2,†, Rineke Steenbergen 3,†, Tyler A. Shaw 4, Tyler M. Renner 1,2
, Peyman Ghorbani 1,2, Mojgan Rezaaifar 1,2, Shauna Han 1,2, Marc-André Langlois 1,2, Angela M. Crawley 1,2,5,6,7, Rodney S. Russell 8, John P. Pezacki 1,2,4, D. Lorne Tyrrell 3 and Morgan D. Fullerton 1,2,*
Kaelan Gobeil Odai 1,2,†, Conor O’Dwyer 1,2,†, Rineke Steenbergen 3,†, Tyler A. Shaw 4, Tyler M. Renner 1,2, Peyman Ghorbani 1,2, Mojgan Rezaaifar 1,2, Shauna Han 1,2, Marc-André Langlois 1,2, Angela M. Crawley 1,2,5,6,7, Rodney S. Russell 8, John P. Pezacki 1,2,4, D. Lorne Tyrrell 3 and Morgan D. Fullerton 1,2,*
1
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
2
University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation, Ottawa, ON K1H 8M5, Canada
3
Department of Medical Microbiology and Immunology and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada
4
Department of Chemistry and Biomolecular Sciences, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
5
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
6
Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
7
Department of Biology, Faculty of Science, Carleton University, Ottawa, ON K1S 5B6, Canada
8
Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Viruses 2020, 12(1), 108; https://doi.org/10.3390/v12010108
Received: 30 December 2019 / Accepted: 13 January 2020 / Published: 16 January 2020
(This article belongs to the Section Antivirals & Vaccines)
Choline is an essential nutrient required for normal neuronal and muscular development, as well as homeostatic regulation of hepatic metabolism. In the liver, choline is incorporated into the main eukaryotic phospholipid, phosphatidylcholine (PC), and can enter one-carbon metabolism via mitochondrial oxidation. Hepatitis C virus (HCV) is a hepatotropic positive-strand RNA virus that similar to other positive-strand RNA viruses and can impact phospholipid metabolism. In the current study we sought to interrogate if HCV modulates markers of choline metabolism following in vitro infection, while subsequently assessing if the inhibition of choline uptake and metabolism upon concurrent HCV infection alters viral replication and infectivity. Additionally, we assessed whether these parameters were consistent between cells cultured in fetal bovine serum (FBS) or human serum (HS), conditions known to differentially affect in vitro HCV infection. We observed that choline transport in FBS- and HS-cultured Huh7.5 cells is facilitated by the intermediate affinity transporter, choline transporter-like family (CTL). HCV infection in FBS, but not HS-cultured cells diminished CTL1 transcript and protein expression at 24 h post-infection, which was associated with lower choline uptake and lower incorporation of choline into PC. No changes in other transporters were observed and at 96 h post-infection, all differences were normalized. Reciprocally, limiting the availability of choline for PC synthesis by use of a choline uptake inhibitor resulted in increased HCV replication at this early stage (24 h post-infection) in both FBS- and HS-cultured cells. Finally, in chronic infection (96 h post-infection), inhibiting choline uptake and metabolism significantly impaired the production of infectious virions. These results suggest that in addition to a known role of choline kinase, the transport of choline, potentially via CTL1, might also represent an important and regulated process during HCV infection.
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Keywords:
choline; hepatitis C virus (HCV); phosphatidylcholine; phospholipids; virus; Huh7.5; CTL1; SLC44A1; immunometabolism
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MDPI and ACS Style
Gobeil Odai, K.; O’Dwyer, C.; Steenbergen, R.; Shaw, T.A.; Renner, T.M.; Ghorbani, P.; Rezaaifar, M.; Han, S.; Langlois, M.-A.; Crawley, A.M.; Russell, R.S.; Pezacki, J.P.; Tyrrell, D.L.; Fullerton, M.D. In Vitro Hepatitis C Virus Infection and Hepatic Choline Metabolism. Viruses 2020, 12, 108.
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