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Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production

Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E(2) (PGE(2)), are known to play important roles in the modulation of both the host re...

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Autores principales: Alfajaro, Mia Madel, Choi, Jong-Soon, Kim, Deok-Song, Seo, Ja-Young, Kim, Ji-Yun, Park, Jun-Gyu, Soliman, Mahmoud, Baek, Yeong-Bin, Cho, Eun-Hyo, Kwon, Joseph, Kwon, Hyung-Jun, Park, Su-Jin, Lee, Woo Song, Kang, Mun-Il, Hosmillo, Myra, Goodfellow, Ian, Cho, Kyoung-Oh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244346/
https://www.ncbi.nlm.nih.gov/pubmed/27881647
http://dx.doi.org/10.1128/JVI.01656-16
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author Alfajaro, Mia Madel
Choi, Jong-Soon
Kim, Deok-Song
Seo, Ja-Young
Kim, Ji-Yun
Park, Jun-Gyu
Soliman, Mahmoud
Baek, Yeong-Bin
Cho, Eun-Hyo
Kwon, Joseph
Kwon, Hyung-Jun
Park, Su-Jin
Lee, Woo Song
Kang, Mun-Il
Hosmillo, Myra
Goodfellow, Ian
Cho, Kyoung-Oh
author_facet Alfajaro, Mia Madel
Choi, Jong-Soon
Kim, Deok-Song
Seo, Ja-Young
Kim, Ji-Yun
Park, Jun-Gyu
Soliman, Mahmoud
Baek, Yeong-Bin
Cho, Eun-Hyo
Kwon, Joseph
Kwon, Hyung-Jun
Park, Su-Jin
Lee, Woo Song
Kang, Mun-Il
Hosmillo, Myra
Goodfellow, Ian
Cho, Kyoung-Oh
author_sort Alfajaro, Mia Madel
collection PubMed
description Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E(2) (PGE(2)), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE(2) pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE(2) production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE(2) pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE(2) pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E(2) (PGE(2)) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE(2) pathway. We further demonstrate that the production of PGE(2) provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.
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spelling pubmed-52443462017-01-30 Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production Alfajaro, Mia Madel Choi, Jong-Soon Kim, Deok-Song Seo, Ja-Young Kim, Ji-Yun Park, Jun-Gyu Soliman, Mahmoud Baek, Yeong-Bin Cho, Eun-Hyo Kwon, Joseph Kwon, Hyung-Jun Park, Su-Jin Lee, Woo Song Kang, Mun-Il Hosmillo, Myra Goodfellow, Ian Cho, Kyoung-Oh J Virol Virus-Cell Interactions Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E(2) (PGE(2)), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE(2) pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE(2) production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE(2) pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE(2) pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. IMPORTANCE Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E(2) (PGE(2)) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE(2) pathway. We further demonstrate that the production of PGE(2) provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection. American Society for Microbiology 2017-01-18 /pmc/articles/PMC5244346/ /pubmed/27881647 http://dx.doi.org/10.1128/JVI.01656-16 Text en Copyright © 2017 Alfajaro et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Virus-Cell Interactions
Alfajaro, Mia Madel
Choi, Jong-Soon
Kim, Deok-Song
Seo, Ja-Young
Kim, Ji-Yun
Park, Jun-Gyu
Soliman, Mahmoud
Baek, Yeong-Bin
Cho, Eun-Hyo
Kwon, Joseph
Kwon, Hyung-Jun
Park, Su-Jin
Lee, Woo Song
Kang, Mun-Il
Hosmillo, Myra
Goodfellow, Ian
Cho, Kyoung-Oh
Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title_full Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title_fullStr Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title_full_unstemmed Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title_short Activation of COX-2/PGE(2) Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production
title_sort activation of cox-2/pge(2) promotes sapovirus replication via the inhibition of nitric oxide production
topic Virus-Cell Interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244346/
https://www.ncbi.nlm.nih.gov/pubmed/27881647
http://dx.doi.org/10.1128/JVI.01656-16
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