Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step

Abstract

Elevated levels of prostaglandins (PGs), products of cyclooxygenases (COXs), are found in the plasma and stool of rotavirus-infected children. We sought to determine the role of COXs, PGs, and the signal transduction pathways involved in rotavirus infection to elucidate possible new targets for antiviral therapy. Human intestinal Caco-2 cells were infected with human rotavirus Wa or simian rotavirus SA-11. COX-2 mRNA expression and secreted PGE 2 levels were determined at different time points postinfection, and the effect of COX inhibitors on rotavirus infection was studied by an immunofluorescence assay (IFA). To reveal the signal transduction pathways involved, the effect of MEK, protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), and NF-B inhibitors on rotavirus infection was analyzed. In infected Caco-2 cells, increased COX-2 mRNA expression and secreted PGE 2 levels were detected. Indomethacin (inhibiting both COX-1 and COX-2) and specific COX-1 and COX-2 inhibitors reduced rotavirus infection by 85 and 50%, respectively, as measured by an IFA. Indomethacin reduced virus infection at a postbinding step early in the infection cycle, inhibiting virus protein synthesis. Indomethacin did not seem to affect viral RNA synthesis. Inhibitors of MEK, PKA, p38 MAPK, and NF-B decreased rotavirus infection by at least 40%. PGE 2 counteracted the effect of the COX and PKA inhibitors but not of the MEK, p38 MAPK, and NF-B inhibitors. Conclusively, COXs and PGE 2 are important mediators of rotavirus infection at a postbinding step. The ERK1/2 pathway mediated by PKA is involved in COX induction by rotavirus infection. MAPK and NF-B pathways are involved in rotavirus infection but in a PGE 2 -independent manner. This report offers new perspectives in the search for therapeutic agents in treatment of severe rotavirus-mediated diarrhea in children.

Active Participation of Cellular Chaperone Hsp90 in Regulating the Function of Rotavirus Nonstructural Protein 3 (NSP3)

“…Rotavirus (RV), 6 a member of the Reoviridae family, is a double-stranded RNA virus associated with severe gastroenteritis in children worldwide (20,21). This virus, with its 11-segmented dsRNA genome, encodes six structural proteins (VP1-VP4, VP6, and VP7), which form the virion, and six nonstructural proteins (NSP1-NSP6), which have a role in improving virus replication and infection in host cells (22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Rotavirus Nonstructural Protein 1 Suppresses Virus-Induced Cellular Apoptosis To Facilitate Viral Growth by Activating the Cell Survival Pathways during Early Stages of Infection

“…Activation of NF-B in HT29 cells after rotavirus infection or only the nonreplicating double-layered particles has been previously reported (37,42). In the present study, we observed sustained activation and nuclear translocation of NF-B after A5-13 infection, which is consistent with previous reports on NF-B activation after rotavirus infection (15,37,42,43). In spite of a previous report of the nuclear translocation of NF-B in A5-16 (24), compared to A5-13, we observed significantly (Ͼ4-fold) lower nuclear translocation of p65 NF-B (Fig.…”

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

“…6) induces viral protein expression. In addition, it has been reported that inhibition of COX activity reduces rotavirus infection 29 ; contrary to that, Chen et al 30 demonstrated that the antiviral action of salicylate is independent of the inhibition of COX activity because the doses used to suppress JEV amplification are higher than those required to inhibit prostaglandin synthesis. In the same study, MAPK inhibitors reversed the antiviral effect of salicylate.…”