Cell culture propagation of foot-and-mouth disease virus: adaptive amino acid substitutions in structural proteins and their functional implications

Abstract

Foot-and-mouth disease is endemic in livestock in large parts of Africa and Asia, where it is an important driver of food insecurity and a major obstacle to agricultural development and the international trade in animal products. Virtually all commercially available vaccines are inactivated whole-virus vaccines produced in cell culture, but the adaptation of a field isolate of the virus to growth in culture is laborious and time-consuming. This is of particular concern for the development of vaccines to newly emerging virus lineages, where long lead times from virus isolate to vaccine can delay the implementation of effective control programs. High antigen yields in production cells are also necessary to make vaccines affordable for less developed countries in endemic areas. Therefore, a rational approach to cell culture adaptation that combines prior knowledge of common adaptive mutations and reverse genetics techniques is urgently required. This review provides an overview of amino acid exchanges in the viral capsid proteins in the context of adaptation to cell culture.

Targeted Modification of the Foot-And-Mouth Disease Virus Genome for Quick Cell Culture Adaptation

“…Asia-Mut 9-4 contains only two amino acid exchanges (Q110K, E202K), unlike Asia-Mut 9-7 that has an additional amino acid exchange (T83A) in VP1. None of the introduced amino acid exchanges are part of any described antigenic site of Asia-1 [32][33][34][35][36][37]. The C-terminus of VP1 has been discussed to be part of the major antigenic site 1 located within the surface-exposed G-H loop [33], but other studies could not confirm the described antigenicity in the context of serotype Asia-1 [32].…”

Single Amino Acid Substitutions Surrounding the Icosahedral Fivefold Symmetry Axis Are Critical for Alternative Receptor Usage of Foot-and-Mouth Disease Virus

“…H108 and T174 were mapped in VP1 of O/HN/CHA/93tc and, instead, the conserved cysteine residues co-existing elsewhere on the FMDV capsid (C2078 and C2130) could tolerate change in the flexibility of the VP1 G–H loop for modulating antigenicity and cell adaptation capacity ( Table S2 ). Clusters of ligand residues overlapping antigenic sites still participate in the compatibility of FMDV with moderate infectivity in tissue culture, by stereo- and electro-chemical modification in ionic, polar and sulfur groups (reviewed in [ 28 ]). As compared with that of O/HN/CHA/93tc, rHN had a relatively lower virulence with a partial loss of antigenicity in vivo [ 34 , 35 ].…”

“…Remarkably, clusters of conserved mutations at or adjacent to the classical RGD motif in the G–H loop of VP1 (130–165 residues) and compensatory replacements (residues 80 in VP2; 173–175 in VP3; 95–98 in VP1) around the VP1 G–H loop of FMDV would ablate integrin interaction that exhibits the non-RGD binding capacity to infect the target cells (reviewed in [ 28 ]). Sa-Carvalho et al and Borca et al have representatively described that one or two residue substitutions in VP3 (H56R) and VP2 (E134K) could play a key role in HS binding of FMDV [ 29 , 30 ].…”

“…Sa-Carvalho et al and Borca et al have representatively described that one or two residue substitutions in VP3 (H56R) and VP2 (E134K) could play a key role in HS binding of FMDV [ 29 , 30 ]. A group of positively charged residue changes (residues 83–85, 108, 110–112 in VP1) surrounding a pore at the icosahedral fivefold axis of the virion might also have great significance for FMDV infection in an RGD- and HS-independent manner (reviewed in [ 28 ]).…”

Sequence Analysis of Egyptian Foot-And-Mouth Disease Virus Field and Vaccine Strains: Intertypic Recombination and Evidence for Accidental Release of Virulent Virus

“…This exchange was maintained over an additional passage in LFBK-αvβ6 cells. Amino acid exchanges in the capsid proteins during cell culture adaptation of field viruses are common, but this is the first description of an exchange at position 9 of VP1 caused by cell culture adaptation of FMDV, and the first report of an N residue at this position [16]. Based on their VP1-coding sequences, the 2016 serotype A FMDV isolates from the Delta region of Egypt from this study are closely related to previously described Egyptian viruses from this time period ( Figure 1), with 99.8% nucleotide sequence identity and 99.0% shared amino acids with FMDV A/Giza 1/EGY/2016 (accession# KX44700).…”