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Picornaviruses are comprised of a positive-sense RNA genome surrounded by a protein shell (or capsid). They are ubiquitous in vertebrates and cause a wide range of important human and animal diseases. The genome encodes a single large polyprotein that is processed to structural (capsid) and non-structural proteins. The non-structural proteins have key functions within the viral replication complex. Some, such as 3Dpol (the RNA dependent RNA polymerase) have conserved functions and participate directly in replicating the viral genome, whereas others, such as 3A, have accessory roles. The 3A proteins are highly divergent across the Picornaviridae and have specific roles both within and outside of the replication complex, which differ between the different genera. These roles include subverting host proteins to generate replication organelles and inhibition of cellular functions (such as protein secretion) to influence virus replication efficiency and the host response to infection. In addition, 3A proteins are associated with the determination of host range. However, recent observations have challenged some of the roles assigned to 3A and suggest that other viral proteins may carry them out. In this review, we revisit the roles of 3A in the picornavirus life cycle. The 3AB precursor and mature 3A have distinct functions during viral replication and, therefore, we have also included discussion of some of the roles assigned to 3AB.
Terry Jackson; Graham Belsham. Picornaviruses: A View from 3A. Viruses 2021, 13, 456 .
AMA StyleTerry Jackson, Graham Belsham. Picornaviruses: A View from 3A. Viruses. 2021; 13 (3):456.
Chicago/Turabian StyleTerry Jackson; Graham Belsham. 2021. "Picornaviruses: A View from 3A." Viruses 13, no. 3: 456.
Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hooved animals that poses a constant burden on farmers in endemic regions and threatens the livestock industries in disease-free countries. Despite the increased number of publicly available whole genome sequences, FMDV data are biased by the opportunistic nature of sampling. Since whole genomic sequences of Southern African Territories (SAT) are particularly underrepresented, this study sequenced 34 isolates from eastern and southern Africa. Phylogenetic analyses revealed two novel genotypes (that comprised 8/34 of these SAT isolates) which contained unusual 5′ untranslated and non-structural encoding regions. While recombination has occurred between these sequences, phylogeny violation analyses indicated that the high degree of sequence diversity for the novel SAT genotypes has not solely arisen from recombination events. Based on estimates of the timing of ancestral divergence, these data are interpreted as being representative of un-sampled FMDV isolates that have been subjected to geographical isolation within Africa by the effects of the Great African Rinderpest Pandemic (1887–1897), which caused a mass die-out of FMDV-susceptible hosts. These findings demonstrate that further sequencing of African FMDV isolates is likely to reveal more unusual genotypes and will allow for better understanding of natural variability and evolution of FMDV.
Lidia Lasecka-Dykes; Caroline F. Wright; Antonello Di Nardo; Grace Logan; Valerie Mioulet; Terry Jackson; Tobias J. Tuthill; Nick J. Knowles; Donald P. King. Full Genome Sequencing Reveals New Southern African Territories Genotypes Bringing Us Closer to Understanding True Variability of Foot-and-Mouth Disease Virus in Africa. Viruses 2018, 10, 192 .
AMA StyleLidia Lasecka-Dykes, Caroline F. Wright, Antonello Di Nardo, Grace Logan, Valerie Mioulet, Terry Jackson, Tobias J. Tuthill, Nick J. Knowles, Donald P. King. Full Genome Sequencing Reveals New Southern African Territories Genotypes Bringing Us Closer to Understanding True Variability of Foot-and-Mouth Disease Virus in Africa. Viruses. 2018; 10 (4):192.
Chicago/Turabian StyleLidia Lasecka-Dykes; Caroline F. Wright; Antonello Di Nardo; Grace Logan; Valerie Mioulet; Terry Jackson; Tobias J. Tuthill; Nick J. Knowles; Donald P. King. 2018. "Full Genome Sequencing Reveals New Southern African Territories Genotypes Bringing Us Closer to Understanding True Variability of Foot-and-Mouth Disease Virus in Africa." Viruses 10, no. 4: 192.
Foot-and-mouth disease (FMD) is endemic in many regions of the world and is one of the most prevalent epizootic animal diseases. FMD affects livestock, such as cattle, sheep, goats and pigs, and causes enormous economic losses due to reduced productivity and trade restrictions. Preparedness and early diagnosis are essential for effective control of FMD. Many diagnostic assays are dependent on raising high-affinity, anti-FMD virus (FMDV) serotype-specific antibodies in small animals (rabbits and guinea pigs) that give broad virus coverage. Here we show that soluble, truncated forms of bovine αvβ6 bind FMDV in an authentic RGD and divalent cation dependent interaction and can be used as the trapping reagent in a FMDV sandwich ELISA. In addition, inclusion of FLAG or His tags facilitates simple purification without the loss of virus binding. We also provide evidence that when combined with a guinea pig polyclonal serum, or serotype-specific monoclonal antibodies, the integrin can be used to detect viruses representative of all FMDV serotypes. We also show that recombinant FMDV empty capsids, with stabilising disulphide bonds, can serve as an antigen in the ELISA and can therefore replace inactivated virus antigen as a positive control for the assay. Our results demonstrate the potential use of bovine αvβ6 and FMDV empty capsids in FMD diagnostic assays.
Gareth Shimmon; Britta A. Wood; Alison Morris; Valerie Mioulet; Santina Grazioli; Emiliana Brocchi; Stephen Berryman; Toby Tuthill; Donald King; Alison Burman; Terry Jackson. Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis. PLOS ONE 2016, 11, e0160696 .
AMA StyleGareth Shimmon, Britta A. Wood, Alison Morris, Valerie Mioulet, Santina Grazioli, Emiliana Brocchi, Stephen Berryman, Toby Tuthill, Donald King, Alison Burman, Terry Jackson. Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis. PLOS ONE. 2016; 11 (8):e0160696.
Chicago/Turabian StyleGareth Shimmon; Britta A. Wood; Alison Morris; Valerie Mioulet; Santina Grazioli; Emiliana Brocchi; Stephen Berryman; Toby Tuthill; Donald King; Alison Burman; Terry Jackson. 2016. "Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis." PLOS ONE 11, no. 8: e0160696.
Vaccination remains the most effective tool for control of foot-and-mouth disease both in endemic countries and as an emergency preparedness for new outbreaks. Foot-and-mouth disease vaccines are chemically inactivated virus preparations and the production of new vaccines is critically dependent upon cell culture adaptation of field viruses, which can prove problematic. A major driver of cell culture adaptation is receptor availability. Field isolates of foot-and-mouth disease virus (FMDV) use RGD-dependent integrins as receptors, whereas cell culture adaptation often selects for variants with altered receptor preferences. Previously, two independent sites on the capsid have been identified where mutations are associated with improved cell culture growth. One is a shallow depression formed by the three major structural proteins (VP1–VP3) where mutations create a heparan sulphate (HS)-binding site (the canonical HS-binding site). The other involves residues of VP1 and is located at the fivefold symmetry axis. For some viruses, changes at this site result in HS binding; for others, the receptors are unknown. Here, we report the identification of a novel site on VP2 where mutations resulted in an expanded cell tropism of a vaccine variant of A/IRN/87 (called A − ). Furthermore, we show that introducing the same mutations into a different type A field virus (A/TUR/2/2006) resulted in the same expanded cell culture tropism as the A/IRN/87 A − vaccine variant. These observations add to the evidence for multiple cell attachment mechanisms for FMDV and may be useful for vaccine manufacture when cell culture adaptation proves difficult.
Kyle Chamberlain; Veronica L. Fowler; Paul V. Barnett; Sarah Gold; Jemma Wadsworth; Nick J. Knowles; Terry Jackson. Identification of a novel cell culture adaptation site on the capsid of foot-and-mouth disease virus. Journal of General Virology 2015, 96, 2684 -2692.
AMA StyleKyle Chamberlain, Veronica L. Fowler, Paul V. Barnett, Sarah Gold, Jemma Wadsworth, Nick J. Knowles, Terry Jackson. Identification of a novel cell culture adaptation site on the capsid of foot-and-mouth disease virus. Journal of General Virology. 2015; 96 (9):2684-2692.
Chicago/Turabian StyleKyle Chamberlain; Veronica L. Fowler; Paul V. Barnett; Sarah Gold; Jemma Wadsworth; Nick J. Knowles; Terry Jackson. 2015. "Identification of a novel cell culture adaptation site on the capsid of foot-and-mouth disease virus." Journal of General Virology 96, no. 9: 2684-2692.
The study of replication of viruses that require high bio-secure facilities can be accomplished with less stringent containment using non-infectious ‘replicon’ systems. The FMDV replicon system (pT7rep) reported by Mclnerney et al. (2000) was modified by the replacement of sequences encoding chloramphenicol acetyl-transferase (CAT) with those encoding a functional L proteinase (Lpro) linked to a bi-functional fluorescent/antibiotic resistance fusion protein (green fluorescent protein/puromycin resistance, [GFP-PAC]). Cells were transfected with replicon-derived transcript RNA and GFP fluorescence quantified. Replication of transcript RNAs was readily detected by fluorescence, whilst the signal from replication-incompetent forms of the genome was >2-fold lower. Surprisingly, a form of the replicon lacking the Lpro showed a significantly stronger fluorescence signal, but appeared with slightly delayed kinetics. Replication can, therefore, be quantified simply by live-cell imaging and image analyses, providing a rapid and facile alternative to RT-qPCR or CAT assays.
Fiona Tulloch; Uday Pathania; Garry A. Luke; John Nicholson; Nicola J. Stonehouse; David J. Rowlands; Terry Jackson; Toby Tuthill; Juergen Haas; Angus I. Lamond; Martin D. Ryan. FMDV replicons encoding green fluorescent protein are replication competent. Journal of Virological Methods 2014, 209, 35 -40.
AMA StyleFiona Tulloch, Uday Pathania, Garry A. Luke, John Nicholson, Nicola J. Stonehouse, David J. Rowlands, Terry Jackson, Toby Tuthill, Juergen Haas, Angus I. Lamond, Martin D. Ryan. FMDV replicons encoding green fluorescent protein are replication competent. Journal of Virological Methods. 2014; 209 ():35-40.
Chicago/Turabian StyleFiona Tulloch; Uday Pathania; Garry A. Luke; John Nicholson; Nicola J. Stonehouse; David J. Rowlands; Terry Jackson; Toby Tuthill; Juergen Haas; Angus I. Lamond; Martin D. Ryan. 2014. "FMDV replicons encoding green fluorescent protein are replication competent." Journal of Virological Methods 209, no. : 35-40.
Picornaviruses replicate their genomes in association with cellular membranes. While enteroviruses are believed to utilize membranes of the early secretory pathway, the origin of the membranes used by foot-and-mouth disease virus (FMDV) for replication are unknown. Secretory-vesicle traffic through the early secretory pathway is mediated by the sequential acquisition of two distinct membrane coat complexes, COPII and COPI, and requires the coordinated actions of Sar1, Arf1 and Rab proteins. Sar1 is essential for generating COPII vesicles at endoplasmic reticulum (ER) exit sites (ERESs), while Arf1 and Rab1 are required for subsequent vesicle transport by COPI vesicles. In the present study, we have provided evidence that FMDV requires pre-Golgi membranes of the early secretory pathway for infection. Small interfering RNA depletion of Sar1 or expression of a dominant-negative (DN) mutant of Sar1a inhibited FMDV infection. In contrast, a dominant-active mutant of Sar1a, which allowed COPII vesicle formation but inhibited the secretory pathway by stabilizing COPII coats, caused major disruption to the ER–Golgi intermediate compartment (ERGIC) but did not inhibit infection. Treatment of cells with brefeldin A, or expression of DN mutants of Arf1 and Rab1a, disrupted the Golgi and enhanced FMDV infection. These results show that reagents that block the early secretory pathway at ERESs have an inhibitory effect on FMDV infection, while reagents that block the early secretory pathway immediately after ER exit but before the ERGIC and Golgi make infection more favourable. Together, these observations argue for a role for Sar1 in FMDV infection and that initial virus replication takes place on membranes that are formed at ERESs.
Rebecca Midgley; Katy Moffat; Stephen Berryman; Philippa Hawes; Jennifer Simpson; Daniel Fullen; David Stephens; Alison Burman; Terry Jackson. A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection. Journal of General Virology 2013, 94, 2636 -2646.
AMA StyleRebecca Midgley, Katy Moffat, Stephen Berryman, Philippa Hawes, Jennifer Simpson, Daniel Fullen, David Stephens, Alison Burman, Terry Jackson. A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection. Journal of General Virology. 2013; 94 (12):2636-2646.
Chicago/Turabian StyleRebecca Midgley; Katy Moffat; Stephen Berryman; Philippa Hawes; Jennifer Simpson; Daniel Fullen; David Stephens; Alison Burman; Terry Jackson. 2013. "A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection." Journal of General Virology 94, no. 12: 2636-2646.
Field isolates of foot-and-mouth disease virus (FMDV) have a restricted cell tropism which is limited by the need for certain RGD-dependent integrin receptors. In contrast, cell culture-adapted viruses use heparan sulfate (HS) or other unidentified molecules as receptors to initiate infection. Here, we report several novel findings resulting from cell culture adaptation of FMDV. In cell culture, a virus with the capsid of the A/Turkey/2/2006 field isolate gained the ability to infect CHO and HS-deficient CHO cells as a result of a single glutamine (Q)-to-lysine (K) substitution at VP1-110 (VP1- Q 110 K ). Using site-directed mutagenesis, the introduction of lysine at this same site also resulted in an acquired ability to infect CHO cells by type O and Asia-1 FMDV. However, this ability appeared to require a second positively charged residue at VP1-109. CHO cells express two RGD-binding integrins (α5β1 and αvβ5) that, although not used by FMDV, have the potential to be used as receptors; however, viruses with the VP1- Q 110 K substitution did not use these integrins. In contrast, the VP1- Q 110 K substitution appeared to result in enhanced interactions with αvβ6, which allowed a virus with KGE in place of the normal RGD integrin-binding motif to use αvβ6 as a receptor. Thus, our results confirmed the existence of nonintegrin, non-HS receptors for FMDV on CHO cells and revealed a novel, non-RGD-dependent use of αvβ6 as a receptor. The introduction of lysine at VP1-110 may allow for cell culture adaptation of FMDV by design, which may prove useful for vaccine manufacture when cell culture adaptation proves intractable.
Stephen Berryman; Stuart Clark; Naresh K. Kakker; Rhiannon Silk; Julian Seago; Jemma Wadsworth; Kyle Chamberlain; Nick J. Knowles; Terry Jackson. Positively Charged Residues at the Five-Fold Symmetry Axis of Cell Culture-Adapted Foot-and-Mouth Disease Virus Permit Novel Receptor Interactions. Journal of Virology 2013, 87, 8735 -8744.
AMA StyleStephen Berryman, Stuart Clark, Naresh K. Kakker, Rhiannon Silk, Julian Seago, Jemma Wadsworth, Kyle Chamberlain, Nick J. Knowles, Terry Jackson. Positively Charged Residues at the Five-Fold Symmetry Axis of Cell Culture-Adapted Foot-and-Mouth Disease Virus Permit Novel Receptor Interactions. Journal of Virology. 2013; 87 (15):8735-8744.
Chicago/Turabian StyleStephen Berryman; Stuart Clark; Naresh K. Kakker; Rhiannon Silk; Julian Seago; Jemma Wadsworth; Kyle Chamberlain; Nick J. Knowles; Terry Jackson. 2013. "Positively Charged Residues at the Five-Fold Symmetry Axis of Cell Culture-Adapted Foot-and-Mouth Disease Virus Permit Novel Receptor Interactions." Journal of Virology 87, no. 15: 8735-8744.
The ability to propagate foot-and-mouth disease virus (FMDV) plays an important role in laboratory diagnosis and the production of vaccines to control the spread of the disease. Many established cell lines suffer from poor sensitivity for isolating virus from field samples. One possible factor that limits sensitivity to FMDV is the lack of expression of surface integrins, the primary class of cell receptor used by FMDV to initiate infection. In this study we have sequenced cDNAs encoding these molecules for pigs and subsequently developed quantitative real-time reverse transcription (RT)-PCR assays to quantify underlying mRNA transcription of integrin molecules. These novel assays were used together with flow-cytometry to determine cell surface expression and of 4 different cell culture systems. These studies have identified a clear correlation of sensitivity to FMDV with expression of integrins αVβ6 and αVβ8. In contrast, cell surface expression of αVβ3 or mRNA for the β1, β3 or β5 subunits did not appear to contribute to sensitivity of cells to FMDV. These findings confirm the requirement for αV6 and αVβ8 as receptors for isolating FMDV from clinical samples and provide important tools and information for the rational design of recombinant cell lines containing these ligands for improved FMDV diagnosis and vaccine production.
Donald P. King; Alison Burman; Sarah Gold; Andrew E. Shaw; Terry Jackson; Nigel P. Ferris. Integrin sub-unit expression in cell cultures used for the diagnosis of foot-and-mouth disease. Veterinary Immunology and Immunopathology 2011, 140, 259 -265.
AMA StyleDonald P. King, Alison Burman, Sarah Gold, Andrew E. Shaw, Terry Jackson, Nigel P. Ferris. Integrin sub-unit expression in cell cultures used for the diagnosis of foot-and-mouth disease. Veterinary Immunology and Immunopathology. 2011; 140 (3-4):259-265.
Chicago/Turabian StyleDonald P. King; Alison Burman; Sarah Gold; Andrew E. Shaw; Terry Jackson; Nigel P. Ferris. 2011. "Integrin sub-unit expression in cell cultures used for the diagnosis of foot-and-mouth disease." Veterinary Immunology and Immunopathology 140, no. 3-4: 259-265.
Attachment of foot-and-mouth disease virus (FMDV) to its cellular receptor involves a long and highly antigenic loop containing the conserved sequence, Arg-Gly-Asp, a motif known to be a recognition element in many integrin-dependent cell adhesion processes. In our original crystal structure of FMDV the Arg-Gly-Asp-containing loop ('the loop'), located between beta-strands G and H of capsid protein VP1, was disordered and hence essentially invisible. We previously surmised that its disorder is enhanced by a disulphide bond linking the base of the loop (Cys 134) to Cys 130 of VP2 (ref. 8). We report here the crystal structure of the virus in which this disulphide is reduced. Reduced virus retains infectivity and serological experiments suggest that some of the loop's internal structure is conserved. But here its structure has become sufficiently ordered to allow us to describe an unambiguous conformation, which we relate to some key biological properties of the virus
Derek Logan; Robin Abu-Ghazaleh; Wendy Blakemore; Stephen Curry; Terry Jackson; Andrew King; Susan Lea; Richard Lewis; John Newman; Nigel Parry; David Rowlands; David Stuart; Elizabeth Fry. Structure of a major immunogenic site on foot-and-mouth disease virus. Nature 1993, 362, 566 -568.
AMA StyleDerek Logan, Robin Abu-Ghazaleh, Wendy Blakemore, Stephen Curry, Terry Jackson, Andrew King, Susan Lea, Richard Lewis, John Newman, Nigel Parry, David Rowlands, David Stuart, Elizabeth Fry. Structure of a major immunogenic site on foot-and-mouth disease virus. Nature. 1993; 362 (6420):566-568.
Chicago/Turabian StyleDerek Logan; Robin Abu-Ghazaleh; Wendy Blakemore; Stephen Curry; Terry Jackson; Andrew King; Susan Lea; Richard Lewis; John Newman; Nigel Parry; David Rowlands; David Stuart; Elizabeth Fry. 1993. "Structure of a major immunogenic site on foot-and-mouth disease virus." Nature 362, no. 6420: 566-568.