title: Cyclosporin a inhibits rotavirus replication and restores interferon-beta signaling pathway in vitro and in vivo.
abstract: Rotavirus (RV) is the most common cause of severe diarrhea among infants and young children. Currently, there is no specific drug available against rotavirus, largely due to the lack of an ideal target molecule which has hampered drug development. Our previous studies have revealed that cyclosporin A (CsA) might be potentially useful as an anti-RV drug. We therefore used both cellular and mouse models to study the immunological safety and effectiveness of CsA as an anti-RV drug. We found that CsA treatment of HT-29 cells before, during, and after viral infection efficiently inhibited Wa strain RV replication and restored IFN-β expression in a HT-29 cell line model. Exploring the underlying mechanisms showed that CsA promoted Interferon Regulatory Factor-5 (IRF-5) expression (a key positive regulator of the type I IFN signaling pathway), but not IRF-1, IRF-3, or IRF-7. Additionally, CsA inhibited SOCS-1 expression (the key negative regulator of IFN-α/β), but not SOCS-2 or SOCS-3. The antiviral effect of CsA was confirmed in an RV-infected neonatal mouse model by evaluation of antigen clearance and assessment of changes in intestinal tissue pathology. Also, no differences in T cell frequency or proliferation between the CsA- and vehicle-treated groups were observed. Thus, both our in vitro and in vivo findings suggest that CsA, through modulating the expression of key regulators in IFN signaling pathway, promote type I IFN-based intracellular innate immunity in RV host cells. These findings suggest that CsA may be a useful candidate to develop a new anti-RV strategy, although further evaluation and characterization of CsA on RV-induced diarrhea are warranted.
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, PR China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Shen
authors.forename: Haiyang
authors.initials: H
authors.lastname: He
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
authors.forename: Jintao
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D003967:Diarrhea / Q000517:prevention & control / Q000821:virology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012401:Rotavirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012400:Rotavirus Infections / Q000517:prevention & control* / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C431713:IRF5 protein, human; D007166:Immunosuppressive Agents; D050835:Interferon Regulatory Factors; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016899:Interferon-beta; D016572:Cyclosporine