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Journal of Virology, September 2004, p. 9721-9730, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9721-9730.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step{dagger}

John W. A. Rossen,* Janneke Bouma, Rolien H. C. Raatgeep, Hans A. Büller, and Alexandra W. C. Einerhand

Laboratory of Pediatrics, Erasmus MC—Sophia Children's Hospital, Rotterdam, The Netherlands

Received 2 February 2004/ Accepted 10 May 2004

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 PGE2 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-{kappa}B inhibitors on rotavirus infection was analyzed. In infected Caco-2 cells, increased COX-2 mRNA expression and secreted PGE2 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-{kappa}B decreased rotavirus infection by at least 40%. PGE2 counteracted the effect of the COX and PKA inhibitors but not of the MEK, p38 MAPK, and NF-{kappa}B inhibitors. Conclusively, COXs and PGE2 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-{kappa}B pathways are involved in rotavirus infection but in a PGE2-independent manner. This report offers new perspectives in the search for therapeutic agents in treatment of severe rotavirus-mediated diarrhea in children.

* Corresponding author. Present address: Department of Virology, Eijkman-Winkler Institute, University Medical Center Utrecht (Rm. G04-614), Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: 31 30 2507627. Fax: 31 30 2541770. E-mail: j.w.a.rossen{at}azu.nl.

{dagger} This paper is dedicated to Bram Rossen.

Journal of Virology, September 2004, p. 9721-9730, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9721-9730.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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