Abstract
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.
Highlights
Human norovirus (HuNoV), a single-stranded, positive sense RNA virus, is a member of the Caliciviridae family
We further investigated if a reverse relationship existed between the cholesterol level and the low-density lipoprotein receptor (LDLR) gene expression in a porcine jejunal epithelial cell line, IPEC-J2, because intestinal epithelial cells are a cell type critical for initiation of human norovirus (HuNoV) infection [16]
Cells were treated with multiple concentrations (0 mM, 1 mM, 20 mM, and 80 mM) of simvastatin, and LDLR gene expression was analyzed by quantitative real-time reverse transcription (RT)-PCR
Summary
Human norovirus (HuNoV), a single-stranded, positive sense RNA virus, is a member of the Caliciviridae family. This virus is the leading pathogen causing food- or water-borne gastroenteritis [1]. Histo-blood group antigens (HBGAs) are considered as cellular receptors or coreceptors that determine host susceptibility to certain HuNoVs. Individuals of blood type A or O (H) of secretors were more susceptible to GI.1/Norwalk/1968/US virus infection than individuals who were non-secretors or secretors of blood type B [9,10]. An emerging HuNoV, GII. strain did not bind to HBGAs when tested in vitro [11] These observations imply a host factor affecting infection by certain genogroups or genotypes of HuNoV
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