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Research Project: National Bio and Agro-Defense Facility Scientists Project

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Title: Understanding the molecular mechanisms of attenuation in codon deoptimized FMDV strains

item Medina, Gisselle
item Spinard Iii, Edward
item Azzinaro, Paul
item RODRIGUEZ-CALZADA, MONICA - Oak Ridge Institute For Science And Education (ORISE)
item Rieder, Aida - Elizabeth
item Diaz San Segundo, Fayna
item De Los Santos, Teresa

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 5/30/2023
Publication Date: 6/6/2023
Citation: Medina, G.N., Spinard Iii, E.J., Azzinaro, P.A., Rodriguez-Calzada, M., Rieder, A.E., Diaz San Segundo, F.C., De Los Santos, T.B. 2023. Understanding the molecular mechanisms of attenuation in codon deoptimized FMDV strains. Meeting Abstract.

Interpretive Summary:

Technical Abstract: Codon-pair deoptimization (CPD) of viral RNA genomes can result in the production of viruses with significant reduction in viral fitness. Recently, we have demonstrated that use of CPD could be considered as a possible approach to develop live-attenuated vaccine (LAV) candidates against foot-and-mouth disease virus (FMDV). Our studies demonstrated that FMDV can tolerate CPD in almost all genomic coding regions resulting in varying degrees of attenuation in vitro and in vivo. Interestingly, the level of attenuation varies depending on the length, location and the FMDV strain/serotype. In this study we show that CPD of the capsid region in FMDV serotypes A24 and Asia1 resulted in viruses significantly attenuated in vivo in swine. However, these LAV candidates did not provide protection against challenge with wild type homologous viruses. To understand the underlying molecular mechanisms of attenuation of FMDV CPD strains, we examined the molecular changes induced by CPD. Our results demonstrate that CPD in FMDV P1 regions results in disruption of RNA secondary structures, unintentional increase in CpG dinucleotide frequencies, significant delay in viral protein expression and inefficient targeting of cellular proteins involved in general translation and antiviral responses (eIF4G, G3BP1/2, PKR, etc). Furthermore, detection of double-stranded RNA as a marker of active replication was severely delayed in CPD viruses when compared to parental strains. Our results suggest that fine tuning of the CPD strategy is necessary to induce a balanced level of attenuation and immunogenicity required for the development of effective FMD LAV candidates.