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A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence

Enteroviruses (EV) are implicated in an extensive range of clinical manifestations, such as pancreatic failure, cardiovascular disease, hepatitis, and meningoencephalitis. We recently reported on the biochemical properties of the highly conserved cysteine residue at position 38 (C38) of enteroviral...

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Autores principales: Voss, Martin, Pinkert, Sandra, Kespohl, Meike, Gimber, Niclas, Klingel, Karin, Schmoranzer, Jan, Laue, Michael, Gaida, Matthias, Kloetzel, Peter-Michael, Beling, Antje
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029043/
https://www.ncbi.nlm.nih.gov/pubmed/35458499
http://dx.doi.org/10.3390/v14040769
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author Voss, Martin
Pinkert, Sandra
Kespohl, Meike
Gimber, Niclas
Klingel, Karin
Schmoranzer, Jan
Laue, Michael
Gaida, Matthias
Kloetzel, Peter-Michael
Beling, Antje
author_facet Voss, Martin
Pinkert, Sandra
Kespohl, Meike
Gimber, Niclas
Klingel, Karin
Schmoranzer, Jan
Laue, Michael
Gaida, Matthias
Kloetzel, Peter-Michael
Beling, Antje
author_sort Voss, Martin
collection PubMed
description Enteroviruses (EV) are implicated in an extensive range of clinical manifestations, such as pancreatic failure, cardiovascular disease, hepatitis, and meningoencephalitis. We recently reported on the biochemical properties of the highly conserved cysteine residue at position 38 (C38) of enteroviral protein 3A and demonstrated a C38-mediated homodimerization of the Coxsackievirus B3 protein 3A (CVB3-3A) that resulted in its profound stabilization. Here, we show that residue C38 of protein 3A supports the replication of CVB3, a clinically relevant member of the enterovirus genus. The infection of HeLa cells with protein 3A cysteine 38 to alanine mutants (C38A) attenuates virus replication, resulting in comparably lower virus particle formation. Consistently, in a mouse infection model, the enhanced virus propagation of CVB3-3A wt in comparison to the CVB3-3A[C38A] mutant was confirmed and found to promote severe liver tissue damage. In contrast, infection with the CVB3-3A[C38A] mutant mitigated hepatic tissue injury and ameliorated the signs of systemic inflammatory responses, such as hypoglycemia and hypothermia. Based on these data and our previous report on the C38-mediated stabilization of the CVB3-3A protein, we conclude that the highly conserved amino acid C38 in protein 3A enhances the virulence of CVB3.
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spelling pubmed-90290432022-04-23 A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence Voss, Martin Pinkert, Sandra Kespohl, Meike Gimber, Niclas Klingel, Karin Schmoranzer, Jan Laue, Michael Gaida, Matthias Kloetzel, Peter-Michael Beling, Antje Viruses Article Enteroviruses (EV) are implicated in an extensive range of clinical manifestations, such as pancreatic failure, cardiovascular disease, hepatitis, and meningoencephalitis. We recently reported on the biochemical properties of the highly conserved cysteine residue at position 38 (C38) of enteroviral protein 3A and demonstrated a C38-mediated homodimerization of the Coxsackievirus B3 protein 3A (CVB3-3A) that resulted in its profound stabilization. Here, we show that residue C38 of protein 3A supports the replication of CVB3, a clinically relevant member of the enterovirus genus. The infection of HeLa cells with protein 3A cysteine 38 to alanine mutants (C38A) attenuates virus replication, resulting in comparably lower virus particle formation. Consistently, in a mouse infection model, the enhanced virus propagation of CVB3-3A wt in comparison to the CVB3-3A[C38A] mutant was confirmed and found to promote severe liver tissue damage. In contrast, infection with the CVB3-3A[C38A] mutant mitigated hepatic tissue injury and ameliorated the signs of systemic inflammatory responses, such as hypoglycemia and hypothermia. Based on these data and our previous report on the C38-mediated stabilization of the CVB3-3A protein, we conclude that the highly conserved amino acid C38 in protein 3A enhances the virulence of CVB3. MDPI 2022-04-07 /pmc/articles/PMC9029043/ /pubmed/35458499 http://dx.doi.org/10.3390/v14040769 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Voss, Martin
Pinkert, Sandra
Kespohl, Meike
Gimber, Niclas
Klingel, Karin
Schmoranzer, Jan
Laue, Michael
Gaida, Matthias
Kloetzel, Peter-Michael
Beling, Antje
A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title_full A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title_fullStr A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title_full_unstemmed A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title_short A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence
title_sort conserved cysteine residue in coxsackievirus b3 protein 3a with implication for elevated virulence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029043/
https://www.ncbi.nlm.nih.gov/pubmed/35458499
http://dx.doi.org/10.3390/v14040769
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