Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids
Rotavirus (RV) primarily infects enterocytes and results in severe diarrhea, particularly in children. It is known that the host immune responses determine the outcome of viral infections. Following infections, interferons (IFNs) are produced as the first and the main anti-viral cytokines to combat the virus. Here we showed that RV predominantly induced type III IFNs (IFN-λ1), and to a less extent, type I IFNs (IFN-α and IFN-β) in human intestinal cells. However, it did not produce detectable IFN proteins and thus, was not sufficient to inhibit RV replication. In contrast, we revealed the essential roles of the basal IFN signaling in limiting RV replication by silencing STAT1, STAT2 and IRF9 genes.
In addition, exogenous IFN treatment demonstrated that RV replication was able to be inhibited by all types of IFNs, both in human intestinal Caco2 cell line and in primary intestinal organoids. In these models, IFNs significantly upregulated a panel of well-known anti-viral IFN-stimulated genes (ISGs). Importantly, inhibition of the JAK-STAT cascade abrogated ISG induction and the anti-RV effects of IFNs. Thus, our study shall contribute to better understanding of the complex RV-host interactions and provide rationale for therapeutic development of IFN-based treatment against RV infection.
|Persistent URL||dx.doi.org/10.1038/s41598-018-26784-9, hdl.handle.net/1765/107331|
Hakim, M.S, Chen, S, Ding, S, Yin, Y, Ikram, A, Ma, X.-X. (Xiao-Xia), … Pan, Q. (2018). Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids. Scientific Reports, 8(1). doi:10.1038/s41598-018-26784-9