Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections

ABSTRACT Viruses of the Enterovirus genus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA...

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Autores principales:	Sonia Maciejewski, Joseph H. C. Nguyen, Fernando Gómez-Herreros, Felipe Cortés-Ledesma, Keith W. Caldecott, Bert L. Semler
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ba5bf0734fdd463c929c7efb532d9693
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spelling	oai:doaj.org-article:ba5bf0734fdd463c929c7efb532d96932021-11-15T15:49:39ZDivergent Requirement for a DNA Repair Enzyme during Enterovirus Infections10.1128/mBio.01931-152150-7511https://doaj.org/article/ba5bf0734fdd463c929c7efb532d96932016-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01931-15https://doaj.org/toc/2150-7511ABSTRACT Viruses of the Enterovirus genus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA repair enzyme known as 5′ tyrosyl-DNA phosphodiesterase 2 (TDP2). TDP2 was previously demonstrated to mediate the cleavage of a unique covalent linkage between a viral protein (VPg) and the 5′ end of picornavirus RNAs. Although VPg is absent from actively translating poliovirus mRNAs, the removal of VPg is not required for the in vitro translation and replication of the RNA. However, TDP2 appears to be excluded from replication and encapsidation sites during peak times of poliovirus infection of HeLa cells, suggesting a role for TDP2 during the viral replication cycle. Using a mouse embryonic fibroblast cell line lacking TDP2, we found that TDP2 is differentially required among enteroviruses. Our single-cycle viral growth analysis shows that CVB3 replication has a greater dependency on TDP2 than does poliovirus or human rhinovirus replication. During infection, CVB3 protein accumulation is undetectable (by Western blot analysis) in the absence of TDP2, whereas poliovirus protein accumulation is reduced but still detectable. Using an infectious CVB3 RNA with a reporter, CVB3 RNA could still be replicated in the absence of TDP2 following transfection, albeit at reduced levels. Overall, these results indicate that TDP2 potentiates viral replication during enterovirus infections of cultured cells, making TDP2 a potential target for antiviral development for picornavirus infections. IMPORTANCE Picornaviruses are one of the most prevalent groups of viruses that infect humans and livestock worldwide. These viruses include the human pathogens belonging to the Enterovirus genus, such as poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus. Diseases caused by enteroviruses pose a major problem for public health and have significant economic impact. Poliovirus can cause paralytic poliomyelitis. CVB3 can cause hand, foot, and mouth disease and myocarditis. Human rhinovirus is the causative agent of the common cold, which has a severe economic impact due to lost productivity and severe health consequences in individuals with respiratory dysfunction, such as asthma. By gaining a better understanding of the enterovirus replication cycle, antiviral drugs against enteroviruses may be developed. Here, we report that the absence of the cellular enzyme TDP2 can significantly decrease viral yields of poliovirus, CVB3, and human rhinovirus, making TDP2 a potential target for an antiviral against enterovirus infections.Sonia MaciejewskiJoseph H. C. NguyenFernando Gómez-HerrerosFelipe Cortés-LedesmaKeith W. CaldecottBert L. SemlerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 1 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sonia Maciejewski Joseph H. C. Nguyen Fernando Gómez-Herreros Felipe Cortés-Ledesma Keith W. Caldecott Bert L. Semler Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
description	ABSTRACT Viruses of the Enterovirus genus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA repair enzyme known as 5′ tyrosyl-DNA phosphodiesterase 2 (TDP2). TDP2 was previously demonstrated to mediate the cleavage of a unique covalent linkage between a viral protein (VPg) and the 5′ end of picornavirus RNAs. Although VPg is absent from actively translating poliovirus mRNAs, the removal of VPg is not required for the in vitro translation and replication of the RNA. However, TDP2 appears to be excluded from replication and encapsidation sites during peak times of poliovirus infection of HeLa cells, suggesting a role for TDP2 during the viral replication cycle. Using a mouse embryonic fibroblast cell line lacking TDP2, we found that TDP2 is differentially required among enteroviruses. Our single-cycle viral growth analysis shows that CVB3 replication has a greater dependency on TDP2 than does poliovirus or human rhinovirus replication. During infection, CVB3 protein accumulation is undetectable (by Western blot analysis) in the absence of TDP2, whereas poliovirus protein accumulation is reduced but still detectable. Using an infectious CVB3 RNA with a reporter, CVB3 RNA could still be replicated in the absence of TDP2 following transfection, albeit at reduced levels. Overall, these results indicate that TDP2 potentiates viral replication during enterovirus infections of cultured cells, making TDP2 a potential target for antiviral development for picornavirus infections. IMPORTANCE Picornaviruses are one of the most prevalent groups of viruses that infect humans and livestock worldwide. These viruses include the human pathogens belonging to the Enterovirus genus, such as poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus. Diseases caused by enteroviruses pose a major problem for public health and have significant economic impact. Poliovirus can cause paralytic poliomyelitis. CVB3 can cause hand, foot, and mouth disease and myocarditis. Human rhinovirus is the causative agent of the common cold, which has a severe economic impact due to lost productivity and severe health consequences in individuals with respiratory dysfunction, such as asthma. By gaining a better understanding of the enterovirus replication cycle, antiviral drugs against enteroviruses may be developed. Here, we report that the absence of the cellular enzyme TDP2 can significantly decrease viral yields of poliovirus, CVB3, and human rhinovirus, making TDP2 a potential target for an antiviral against enterovirus infections.
format	article
author	Sonia Maciejewski Joseph H. C. Nguyen Fernando Gómez-Herreros Felipe Cortés-Ledesma Keith W. Caldecott Bert L. Semler
author_facet	Sonia Maciejewski Joseph H. C. Nguyen Fernando Gómez-Herreros Felipe Cortés-Ledesma Keith W. Caldecott Bert L. Semler
author_sort	Sonia Maciejewski
title	Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
title_short	Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
title_full	Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
title_fullStr	Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
title_full_unstemmed	Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections
title_sort	divergent requirement for a dna repair enzyme during enterovirus infections
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/ba5bf0734fdd463c929c7efb532d9693
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Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections

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