Abstract
Norovirus is the leading cause of acute gastroenteritis worldwide. The pathogenesis of norovirus and the induced immune response remain poorly understood due to the lack of a robust virus culture system. The monolayers of two secretor-positive Chinese human intestinal enteroid (HIE) lines were challenged with two norovirus pandemic GII.4 Sydney strains. Norovirus RNA replication in supernatants and cell lysates were quantified by RT-qPCR. RNA expression levels of immune-related genes were profiled using PCR arrays. The secreted protein levels of shortlisted upregulated genes were measured in supernatants using analyte-specific enzyme-linked immunosorbent assay (ELISA). Productive norovirus replications were achieved in three (75%) out of four inoculations. The two most upregulated immune-related genes were CXCL10 (93-folds) and IFI44L (580-folds). Gene expressions of CXCL10 and IFI44L were positively correlated with the level of norovirus RNA replication (CXCL10: Spearman’s r = 0.779, p < 0.05; IFI44L: r = 0.881, p < 0.01). The higher level of secreted CXCL10 and IFI44L proteins confirmed their elevated gene expression. The two genes have been reported to be upregulated in norovirus volunteer challenges and natural human infections by other viruses. Our data suggested that HIE could mimic the innate immune response elicited in natural norovirus infection and, therefore, could serve as an experimental model for future virus-host interaction and antiviral studies.
Highlights
Human norovirus (HuNoV) is the leading cause of acute viral gastroenteritis worldwide
Since histo-blood group antigens (HBGAs) in the host are hypothesized to contribute towards host susceptibility to HuNoV infection, considering the secretor status of the human intestinal enteroid (HIE) line being established, CUHK-ED-2 and CUHK-ED-3 were used for HuNoV inoculation
The current understanding of pathogenesis and immune response induced by HuNoV is still limited due to the inability in cultivating HuNoV with a robust and reproducible model
Summary
Human norovirus (HuNoV) is the leading cause of acute viral gastroenteritis worldwide. Norovirus is currently classified into ten genogroups (GI–GX) based on the sequence variation of the capsid protein (VP1) and the RNA-dependent RNA polymerase and is further subdivided into 48 genotypes (e.g., GI. and GII.4) [1]. Among all the genotypes that are associated with human infection, strains of the GII. genotype are the most predominant [11] and have attributed to 70–80% of all reported outbreaks in past decades [12]. Every two to three years, the genotype GII. undergoes epochal evolution and new variants often emerge [13]. A total of six immune-escaped variants of the GII. genotypes have evolved since 1995 and have resulted in pandemics across the world [14,15], whereas GII..
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