Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.

Defensins are effectors of the innate immune response with potent antibacterial activity. Their role in antiviral immunity, particularly for non-enveloped viruses, is poorly understood. We recently found that human alpha-defensins inhibit human adenovirus (HAdV) by preventing virus uncoating and rel...

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Autores principales:	Jason G Smith, Mariena Silvestry, Steffen Lindert, Wuyuan Lu, Glen R Nemerow, Phoebe L Stewart
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f8303a732833465089b6356b5079e7a6
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spelling	oai:doaj.org-article:f8303a732833465089b6356b5079e7a62021-12-02T20:00:32ZInsight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.1553-73661553-737410.1371/journal.ppat.1000959https://doaj.org/article/f8303a732833465089b6356b5079e7a62010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20585634/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Defensins are effectors of the innate immune response with potent antibacterial activity. Their role in antiviral immunity, particularly for non-enveloped viruses, is poorly understood. We recently found that human alpha-defensins inhibit human adenovirus (HAdV) by preventing virus uncoating and release of the endosomalytic protein VI during cell entry. Consequently, AdV remains trapped in the endosomal/lysosomal pathway rather than trafficking to the nucleus. To gain insight into the mechanism of defensin-mediated neutralization, we analyzed the specificity of the AdV-defensin interaction. Sensitivity to alpha-defensin neutralization is a common feature of HAdV species A, B1, B2, C, and E, whereas species D and F are resistant. Thousands of defensin molecules bind with low micromolar affinity to a sensitive serotype, but only a low level of binding is observed to resistant serotypes. Neutralization is dependent upon a correctly folded defensin molecule, suggesting that specific molecular interactions occur with the virion. CryoEM structural studies and protein sequence analysis led to a hypothesis that neutralization determinants are located in a region spanning the fiber and penton base proteins. This model was supported by infectivity studies using virus chimeras comprised of capsid proteins from sensitive and resistant serotypes. These findings suggest a mechanism in which defensin binding to critical sites on the AdV capsid prevents vertex removal and thereby blocks subsequent steps in uncoating that are required for release of protein VI and endosomalysis during infection. In addition to informing the mechanism of defensin-mediated neutralization of a non-enveloped virus, these studies provide insight into the mechanism of AdV uncoating and suggest new strategies to disrupt this process and inhibit infection.Jason G SmithMariena SilvestrySteffen LindertWuyuan LuGlen R NemerowPhoebe L StewartPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 6, p e1000959 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jason G Smith Mariena Silvestry Steffen Lindert Wuyuan Lu Glen R Nemerow Phoebe L Stewart Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
description	Defensins are effectors of the innate immune response with potent antibacterial activity. Their role in antiviral immunity, particularly for non-enveloped viruses, is poorly understood. We recently found that human alpha-defensins inhibit human adenovirus (HAdV) by preventing virus uncoating and release of the endosomalytic protein VI during cell entry. Consequently, AdV remains trapped in the endosomal/lysosomal pathway rather than trafficking to the nucleus. To gain insight into the mechanism of defensin-mediated neutralization, we analyzed the specificity of the AdV-defensin interaction. Sensitivity to alpha-defensin neutralization is a common feature of HAdV species A, B1, B2, C, and E, whereas species D and F are resistant. Thousands of defensin molecules bind with low micromolar affinity to a sensitive serotype, but only a low level of binding is observed to resistant serotypes. Neutralization is dependent upon a correctly folded defensin molecule, suggesting that specific molecular interactions occur with the virion. CryoEM structural studies and protein sequence analysis led to a hypothesis that neutralization determinants are located in a region spanning the fiber and penton base proteins. This model was supported by infectivity studies using virus chimeras comprised of capsid proteins from sensitive and resistant serotypes. These findings suggest a mechanism in which defensin binding to critical sites on the AdV capsid prevents vertex removal and thereby blocks subsequent steps in uncoating that are required for release of protein VI and endosomalysis during infection. In addition to informing the mechanism of defensin-mediated neutralization of a non-enveloped virus, these studies provide insight into the mechanism of AdV uncoating and suggest new strategies to disrupt this process and inhibit infection.
format	article
author	Jason G Smith Mariena Silvestry Steffen Lindert Wuyuan Lu Glen R Nemerow Phoebe L Stewart
author_facet	Jason G Smith Mariena Silvestry Steffen Lindert Wuyuan Lu Glen R Nemerow Phoebe L Stewart
author_sort	Jason G Smith
title	Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
title_short	Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
title_full	Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
title_fullStr	Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
title_full_unstemmed	Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
title_sort	insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/f8303a732833465089b6356b5079e7a6
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Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.

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