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Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)

Marek’s disease virus (MDV) causes deadly lymphoma and induces an imbalance of the lipid metabolism in infected chickens. Here, we discovered that MDV activates the fatty acid synthesis (FAS) pathway in primary chicken embryo fibroblasts (CEFs). In addition, MDV-infected cells contained high levels...

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Autores principales: Boodhoo, Nitish, Kamble, Nitin, Kaufer, Benedikt B., Behboudi, Shahriar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580946/
https://www.ncbi.nlm.nih.gov/pubmed/30971474
http://dx.doi.org/10.1128/JVI.00352-19
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author Boodhoo, Nitish
Kamble, Nitin
Kaufer, Benedikt B.
Behboudi, Shahriar
author_facet Boodhoo, Nitish
Kamble, Nitin
Kaufer, Benedikt B.
Behboudi, Shahriar
author_sort Boodhoo, Nitish
collection PubMed
description Marek’s disease virus (MDV) causes deadly lymphoma and induces an imbalance of the lipid metabolism in infected chickens. Here, we discovered that MDV activates the fatty acid synthesis (FAS) pathway in primary chicken embryo fibroblasts (CEFs). In addition, MDV-infected cells contained high levels of fatty acids and showed increased numbers of lipid droplets (LDs). Chemical inhibitors of the FAS pathway (TOFA and C75) reduced MDV titers by approximately 30-fold. Addition of the downstream metabolites, including malonyl-coenzyme A and palmitic acid, completely restored the inhibitory effects of the FAS inhibitors. Furthermore, we could demonstrate that MDV infection activates the COX-2/prostaglandin E(2) (PGE(2)) pathway, as evident by increased levels of arachidonic acid, COX-2 expression, and PGE(2) synthesis. Inhibition of the COX-2/PGE(2) pathway by chemical inhibitors or knockdown of COX2 using short hairpin RNA reduced MDV titers, suggesting that COX-2 promotes virus replication. Exogenous PGE(2) completely restored the inhibition of the COX-2/PGE(2) pathway in MDV replication. Unexpectedly, exogenous PGE(2) also partially rescued the inhibitory effects of FAS inhibitors on MDV replication, suggesting that there is a link between these two pathways in MDV infection. Taken together, our data demonstrate that the FAS and COX-2/PGE(2) pathways play an important role in the replication of this deadly pathogen. IMPORTANCE Disturbances of the lipid metabolism in chickens infected with MDV contribute to the pathogenesis of disease. However, the role of lipid metabolism in MDV replication remained unknown. Here, we demonstrate that MDV infection activates FAS and induces LD formation. Moreover, our results demonstrate that MDV replication is highly dependent on the FAS pathway and the downstream metabolites. Finally, our results reveal that MDV also activates the COX-2/PGE(2) pathway, which supports MDV replication by activating PGE(2)/EP2 and PGE(2)/EP4 signaling pathways.
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spelling pubmed-65809462019-07-03 Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2) Boodhoo, Nitish Kamble, Nitin Kaufer, Benedikt B. Behboudi, Shahriar J Virol Virus-Cell Interactions Marek’s disease virus (MDV) causes deadly lymphoma and induces an imbalance of the lipid metabolism in infected chickens. Here, we discovered that MDV activates the fatty acid synthesis (FAS) pathway in primary chicken embryo fibroblasts (CEFs). In addition, MDV-infected cells contained high levels of fatty acids and showed increased numbers of lipid droplets (LDs). Chemical inhibitors of the FAS pathway (TOFA and C75) reduced MDV titers by approximately 30-fold. Addition of the downstream metabolites, including malonyl-coenzyme A and palmitic acid, completely restored the inhibitory effects of the FAS inhibitors. Furthermore, we could demonstrate that MDV infection activates the COX-2/prostaglandin E(2) (PGE(2)) pathway, as evident by increased levels of arachidonic acid, COX-2 expression, and PGE(2) synthesis. Inhibition of the COX-2/PGE(2) pathway by chemical inhibitors or knockdown of COX2 using short hairpin RNA reduced MDV titers, suggesting that COX-2 promotes virus replication. Exogenous PGE(2) completely restored the inhibition of the COX-2/PGE(2) pathway in MDV replication. Unexpectedly, exogenous PGE(2) also partially rescued the inhibitory effects of FAS inhibitors on MDV replication, suggesting that there is a link between these two pathways in MDV infection. Taken together, our data demonstrate that the FAS and COX-2/PGE(2) pathways play an important role in the replication of this deadly pathogen. IMPORTANCE Disturbances of the lipid metabolism in chickens infected with MDV contribute to the pathogenesis of disease. However, the role of lipid metabolism in MDV replication remained unknown. Here, we demonstrate that MDV infection activates FAS and induces LD formation. Moreover, our results demonstrate that MDV replication is highly dependent on the FAS pathway and the downstream metabolites. Finally, our results reveal that MDV also activates the COX-2/PGE(2) pathway, which supports MDV replication by activating PGE(2)/EP2 and PGE(2)/EP4 signaling pathways. American Society for Microbiology 2019-06-14 /pmc/articles/PMC6580946/ /pubmed/30971474 http://dx.doi.org/10.1128/JVI.00352-19 Text en Copyright © 2019 Boodhoo et al. https://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 (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Virus-Cell Interactions
Boodhoo, Nitish
Kamble, Nitin
Kaufer, Benedikt B.
Behboudi, Shahriar
Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title_full Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title_fullStr Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title_full_unstemmed Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title_short Replication of Marek's Disease Virus Is Dependent on Synthesis of De Novo Fatty Acid and Prostaglandin E(2)
title_sort replication of marek's disease virus is dependent on synthesis of de novo fatty acid and prostaglandin e(2)
topic Virus-Cell Interactions
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580946/
https://www.ncbi.nlm.nih.gov/pubmed/30971474
http://dx.doi.org/10.1128/JVI.00352-19
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