The effects of simvastatin or interferon-α on infectivity of human norovirus using a gnotobiotic pig model for the study of antivirals.
The lack of an animal model for human norovirus (HuNoV) has hindered the development of therapeutic strategies. This study demonstrated that a commonly used cholesterol-lowering statin medication, simvastatin, which increases HuNoV replication in an in vitro replicon system, also enhances HuNoV infectivity in the gnotobiotic (Gn) pig model. In contrast, oral treatment with interferon (IFN)-α reduces HuNoV infectivity. Young piglets, all with A or H1 histo-blood group antigens on enterocytes, were treated orally with 8 mg/kg/day of simvastatin; 5 days later, the pigs were inoculated orally with a GII.4 HuNoV (HS194/2009/US strain) and then treated with simvastatin for 5 more days. Simvastatin induced significantly earlier onset and longer duration of HuNoV fecal shedding in treated pigs, frequently with higher fecal viral titers. Simvastatin impaired poly (I:C)-induced IFN-α expression in macrophages or dendritic cells, possibly due to lowered toll-like receptor (TLR) 3 expression; however, the mechanisms were not related to interferon regulatory factor 3 or nuclear factor kappa B signaling pathway. Thus, the enhanced, earlier infectivity of HuNoV in simvastatin-treated pigs coincided with the inhibitory effect of simvastatin on innate immunity. In contrast to the increased HuNoV shedding that simvastatin induced, viral shedding during the treatment period was reduced or curtailed in the HuNoV-inoculated pigs pre-treated/treated with human IFN-α. Our findings are the first to indicate that IFN-α has potential as antiviral therapy against HuNoV. Based on these intriguing and novel findings using the Gn pig model, we confirmed that HuNoV infectivity is altered by treatment with simvastatin or IFN-α. Collectively, these findings indicate that Gn pigs are a useful model to test immunomodulators or efficacy of antivirals against HuNoV.
Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio, United States of America.
Kwonil
K
Jung
Qiuhong
Q
Wang
Yunjeong
Y
Kim
Kelly
K
Scheuer
Zhenwen
Z
Zhang
Quan
Q
Shen
Kyeong-Ok
KO
Chang
Linda J
LJ
Saif
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001789:Blood Group Antigens / Q000378:metabolism; D017250:Caliciviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D002784:Cholesterol / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects / Q000821:virology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000821:virology; D005786:Gene Expression Regulation / Q000187:drug effects; D005856:Germ-Free Life / Q000187:drug effects*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D029322:Norovirus / Q000187:drug effects / Q000472:pathogenicity*; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D034421:Sus scrofa / Q000097:blood / Q000821:virology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D017201:Virus Shedding / Q000187:drug effects
D000998:Antiviral Agents; D001789:Blood Group Antigens; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D016328:NF-kappa B; D011973:Receptors, LDL; D051196:Toll-Like Receptor 3; D002784:Cholesterol; D019821:Simvastatin