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Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation

Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks i...

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Autores principales: Medina, Gisselle N., Spinard, Edward, Azzinaro, Paul A., Rodriguez-Calzada, Monica, Gutkoska, Joseph, Kloc, Anna, Rieder, Elizabeth A., Taillon, Bruce E., Mueller, Stephen, de los Santos, Teresa, Segundo, Fayna Diaz-San
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301631/
https://www.ncbi.nlm.nih.gov/pubmed/37376631
http://dx.doi.org/10.3390/v15061332
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author Medina, Gisselle N.
Spinard, Edward
Azzinaro, Paul A.
Rodriguez-Calzada, Monica
Gutkoska, Joseph
Kloc, Anna
Rieder, Elizabeth A.
Taillon, Bruce E.
Mueller, Stephen
de los Santos, Teresa
Segundo, Fayna Diaz-San
author_facet Medina, Gisselle N.
Spinard, Edward
Azzinaro, Paul A.
Rodriguez-Calzada, Monica
Gutkoska, Joseph
Kloc, Anna
Rieder, Elizabeth A.
Taillon, Bruce E.
Mueller, Stephen
de los Santos, Teresa
Segundo, Fayna Diaz-San
author_sort Medina, Gisselle N.
collection PubMed
description Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks in endemic settings. Previously, we employed two distinct strategies (codon pair bias deoptimization (CPD) and codon bias deoptimization (CD)) to deoptimize various regions of the FMDV serotype A subtype A12 genome, which resulted in the development of an attenuated virus in vitro and in vivo, inducing varying levels of humoral responses. In the current study, we examined the versatility of the system by using CPD applied to the P1 capsid coding region of FMDV serotype A subtype, A24, and another serotype, Asia1. Viruses carrying recoded P1 (A24-P1Deopt or Asia1-P1Deopt) exhibited different degrees of attenuation (i.e., delayed viral growth kinetics and replication) in cultured cells. Studies in vivo using a mouse model of FMD demonstrated that inoculation with the A24-P1Deopt and Asia1-P1Deopt strains elicited a strong humoral immune response capable of offering protection against challenge with homologous wildtype (WT) viruses. However, different results were obtained in pigs. While clear attenuation was detected for both the A24-P1Deopt and Asia1-P1Deopt strains, only a limited induction of adaptive immunity and protection against challenge was detected, depending on the inoculated dose and serotype deoptimized. Our work demonstrates that while CPD of the P1 coding region attenuates viral strains of multiple FMDV serotypes/subtypes, a thorough assessment of virulence and induction of adaptive immunity in the natural host is required in each case in order to finely adjust the degree of deoptimization required for attenuation without affecting the induction of protective adaptive immune responses.
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spelling pubmed-103016312023-06-29 Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation Medina, Gisselle N. Spinard, Edward Azzinaro, Paul A. Rodriguez-Calzada, Monica Gutkoska, Joseph Kloc, Anna Rieder, Elizabeth A. Taillon, Bruce E. Mueller, Stephen de los Santos, Teresa Segundo, Fayna Diaz-San Viruses Article Foot-and-mouth disease (FMD), caused by the FMD virus (FMDV), is a highly contagious disease of cloven-hoofed livestock that can have severe economic impacts. Control and prevention strategies, including the development of improved vaccines, are urgently needed to effectively control FMD outbreaks in endemic settings. Previously, we employed two distinct strategies (codon pair bias deoptimization (CPD) and codon bias deoptimization (CD)) to deoptimize various regions of the FMDV serotype A subtype A12 genome, which resulted in the development of an attenuated virus in vitro and in vivo, inducing varying levels of humoral responses. In the current study, we examined the versatility of the system by using CPD applied to the P1 capsid coding region of FMDV serotype A subtype, A24, and another serotype, Asia1. Viruses carrying recoded P1 (A24-P1Deopt or Asia1-P1Deopt) exhibited different degrees of attenuation (i.e., delayed viral growth kinetics and replication) in cultured cells. Studies in vivo using a mouse model of FMD demonstrated that inoculation with the A24-P1Deopt and Asia1-P1Deopt strains elicited a strong humoral immune response capable of offering protection against challenge with homologous wildtype (WT) viruses. However, different results were obtained in pigs. While clear attenuation was detected for both the A24-P1Deopt and Asia1-P1Deopt strains, only a limited induction of adaptive immunity and protection against challenge was detected, depending on the inoculated dose and serotype deoptimized. Our work demonstrates that while CPD of the P1 coding region attenuates viral strains of multiple FMDV serotypes/subtypes, a thorough assessment of virulence and induction of adaptive immunity in the natural host is required in each case in order to finely adjust the degree of deoptimization required for attenuation without affecting the induction of protective adaptive immune responses. MDPI 2023-06-06 /pmc/articles/PMC10301631/ /pubmed/37376631 http://dx.doi.org/10.3390/v15061332 Text en © 2023 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
Medina, Gisselle N.
Spinard, Edward
Azzinaro, Paul A.
Rodriguez-Calzada, Monica
Gutkoska, Joseph
Kloc, Anna
Rieder, Elizabeth A.
Taillon, Bruce E.
Mueller, Stephen
de los Santos, Teresa
Segundo, Fayna Diaz-San
Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title_full Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title_fullStr Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title_full_unstemmed Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title_short Deoptimization of FMDV P1 Region Results in Robust Serotype-Independent Viral Attenuation
title_sort deoptimization of fmdv p1 region results in robust serotype-independent viral attenuation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301631/
https://www.ncbi.nlm.nih.gov/pubmed/37376631
http://dx.doi.org/10.3390/v15061332
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