Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability
Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid. This acid lability is directly related to its mechanism of uncoating triggered by acidification inside cellular endosomes. Using a collection of FMDV mutants we have systematically analyzed the relationship between acid stability and the requirement for acidic endosomes using ammonium chloride (NH4Cl), an inhibitor of endosome acidification. A FMDV mutant carrying two substitutions with opposite effects on acid-stability (VP3 A116V that reduces acid stability, and VP1 N17D that increases acid stability) displayed a rapid shift towards acid lability that resulted in increased resistance to NH4Cl as well as to concanamicyn A, a different lysosomotropic agent. This resistance could be explained by a higher ability of the mutant populations to produce NH4Cl-resistant variants, as supported by their tendency to accumulate mutations related to NH4Cl-resistance that was higher than that of the WT populations. Competition experiments also indicated that the combination of both amino acid substitutions promoted an increase of viral fitness that likely contributed to NH4Cl resistance. This study provides novel evidences supporting that the combination of mutations in a viral capsid can result in compensatory effects that lead to fitness gain, and facilitate space to an inhibitor of acid-dependent uncoating. Thus, although drug-resistant variants usually exhibit a reduction in viral fitness, our results indicate that compensatory mutations that restore this reduction in fitness can promote emergence of resistance mutants
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Springer Nature
2021
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Online Access: | http://hdl.handle.net/10261/262392 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/100012818 http://dx.doi.org/10.13039/501100003339 |
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dig-inia-es-10261-2623922023-01-30T11:38:38Z Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability Caridi, Flavia Cañas-Arranz, Rodrigo Vázquez-Calvo, Ángela León, Patricia de Calderón, Katherine L. Domingo, Esteban Sobrino Castelló, Francisco Martín-Acebes, Miguel Ángel Comunidad de Madrid Ministerio de Economía y Competitividad (España) Consejo Superior de Investigaciones Científicas (España) Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid. This acid lability is directly related to its mechanism of uncoating triggered by acidification inside cellular endosomes. Using a collection of FMDV mutants we have systematically analyzed the relationship between acid stability and the requirement for acidic endosomes using ammonium chloride (NH4Cl), an inhibitor of endosome acidification. A FMDV mutant carrying two substitutions with opposite effects on acid-stability (VP3 A116V that reduces acid stability, and VP1 N17D that increases acid stability) displayed a rapid shift towards acid lability that resulted in increased resistance to NH4Cl as well as to concanamicyn A, a different lysosomotropic agent. This resistance could be explained by a higher ability of the mutant populations to produce NH4Cl-resistant variants, as supported by their tendency to accumulate mutations related to NH4Cl-resistance that was higher than that of the WT populations. Competition experiments also indicated that the combination of both amino acid substitutions promoted an increase of viral fitness that likely contributed to NH4Cl resistance. This study provides novel evidences supporting that the combination of mutations in a viral capsid can result in compensatory effects that lead to fitness gain, and facilitate space to an inhibitor of acid-dependent uncoating. Thus, although drug-resistant variants usually exhibit a reduction in viral fitness, our results indicate that compensatory mutations that restore this reduction in fitness can promote emergence of resistance mutants Comunidad de Madrid co-financed with ECFEDER funds (P2018/BAA-4370). Work in F.S.’s laboratory was also funded by Grants from MINECO/MICINN-FEDER EU (AGL2017-84097-C2-1-R; PID2020-113184RB-C21), and through the Spanish National Reserarch Council (CSIC), grant CONEXIONES-Vida/202120E47. Work in E.D.´s laboratory was also funded by MICIN/-FEDER 2022-03-01T12:30:11Z 2022-03-01T12:30:11Z 2021 2022-03-01T12:30:11Z artículo http://purl.org/coar/resource_type/c_6501 doi: 10.1038/s41598-021-02757-3 issn: 2045-2322 Scientific Reports 11: 2349 (2021) http://hdl.handle.net/10261/262392 10.1038/s41598-021-02757-3 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/100012818 http://dx.doi.org/10.13039/501100003339 Publisher's version http://dx.doi.org/10.1038/s41598-021-02757-3 Sí open Springer Nature |
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Foot-and-mouth disease virus (FMDV) is a picornavirus that exhibits an extremely acid sensitive capsid. This acid lability is directly related to its mechanism of uncoating triggered by acidification inside cellular endosomes. Using a collection of FMDV mutants we have systematically analyzed the relationship between acid stability and the requirement for acidic endosomes using ammonium chloride (NH4Cl), an inhibitor of endosome acidification. A FMDV mutant carrying two substitutions with opposite effects on acid-stability (VP3 A116V that reduces acid stability, and VP1 N17D that increases acid stability) displayed a rapid shift towards acid lability that resulted in increased resistance to NH4Cl as well as to concanamicyn A, a different lysosomotropic agent. This resistance could be explained by a higher ability of the mutant populations to produce NH4Cl-resistant variants, as supported by their tendency to accumulate mutations related to NH4Cl-resistance that was higher than that of the WT populations. Competition experiments also indicated that the combination of both amino acid substitutions promoted an increase of viral fitness that likely contributed to NH4Cl resistance. This study provides novel evidences supporting that the combination of mutations in a viral capsid can result in compensatory effects that lead to fitness gain, and facilitate space to an inhibitor of acid-dependent uncoating. Thus, although drug-resistant variants usually exhibit a reduction in viral fitness, our results indicate that compensatory mutations that restore this reduction in fitness can promote emergence of resistance mutants |
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Comunidad de Madrid |
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Comunidad de Madrid Caridi, Flavia Cañas-Arranz, Rodrigo Vázquez-Calvo, Ángela León, Patricia de Calderón, Katherine L. Domingo, Esteban Sobrino Castelló, Francisco Martín-Acebes, Miguel Ángel |
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artículo |
author |
Caridi, Flavia Cañas-Arranz, Rodrigo Vázquez-Calvo, Ángela León, Patricia de Calderón, Katherine L. Domingo, Esteban Sobrino Castelló, Francisco Martín-Acebes, Miguel Ángel |
spellingShingle |
Caridi, Flavia Cañas-Arranz, Rodrigo Vázquez-Calvo, Ángela León, Patricia de Calderón, Katherine L. Domingo, Esteban Sobrino Castelló, Francisco Martín-Acebes, Miguel Ángel Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
author_sort |
Caridi, Flavia |
title |
Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
title_short |
Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
title_full |
Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
title_fullStr |
Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
title_full_unstemmed |
Adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
title_sort |
adaptive value of foot-and-mouth disease virus capsid substitutions with opposite effects on particle acid stability |
publisher |
Springer Nature |
publishDate |
2021 |
url |
http://hdl.handle.net/10261/262392 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/100012818 http://dx.doi.org/10.13039/501100003339 |
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