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[Foot and mouth disease: epidemiological considerations, virological and immunological lessons from a large outbreak].
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Evidence of partial protection against foot-and-mouth disease in cattle immunized with a recombinant adenovirus vector expressing the precursor polypeptide (P1) of foot-and-mouth disease virus capsid proteins.
A recombinant live vector vaccine was produced by insertion of cDNA encoding the structural proteins (P1) of foot-and-mouth disease virus (FMDV) into a replication-competent human adenovirus type 5 vaccine strain (Ad5 wt). Groups of cattle (n = 3) were immunized twice, by the subcutaneous and/or intranasal routes, with either the Ad5 wt vaccine or with the recombinant FMDV Ad5-P1 vaccine. All animals were challenged by intranasal instillation of FMDV 4 weeks after the second immunizations. In the absence of a detectable antibody response to FMDV, significant protection against viral challenge was seen in all of the animals immunized twice by the subcutaneous route with the recombinant vaccine. The observed partial protection against clinical disease was not associated with a reduction in titre of persistent FMDV infections in the oropharynx of challenged cattle.
Construction of a chimeric Theiler's murine encephalomyelitis virus containing the leader gene of foot-and-mouth disease virus.
The foot-and-mouth disease virus (FMDV) leader coding region (Lb) was cloned into a full-length cDNA of the DA strain of Theiler's murine encephalomyelitis virus (TMEV) replacing the complete L coding region of TMEV. This construct, pDAFSSC1-Lb, was engineered to contain cleavage sites, at the 3' end of the Lb coding region, for both the FMDV Lb and the TMEV 3C proteases. Transcripts derived from this construct were translated in a cell-free system. Analysis of the translation products showed efficient synthesis and processing of TMEV structural and nonstructural proteins as well as a major band that comigrated with FMDV Lb and was reactive with Lb antiserum. A small plaque virus was recovered from BHK-21 cells transfected with RNA derived from pDAFSSC1-Lb. RT-PCR of RNA isolated from DAFSSC1-Lb virus demonstrated a product corresponding in size and sequence to FMDV Lb. DAFSSC1-Lb virus grew slower than parental virus, DAFSSC1, and to a lower titer. The pattern of viral proteins synthesized in DAFSSC1-Lb virus-infected cells was very similar to the pattern in DAFSSC1 virus-infected cells except that significant amounts of FMDV Lb were produced. In addition, extracts from DAFSSC1-Lb-virus-infected cells cleaved an exogenous source of the translation initiation factor, p220, while DAFSSC1-virus-infected extracts did not. Chimeric viruses that contain coding regions from different picornaviral genera may be valuable tools in investigating the function of particular viral proteins and in studying disease pathogenesis.
Detection and characterization of functional T-cell epitopes on the structural proteins VP2, VP3, and VP4 of foot and mouth disease virus O1 campos.
Foot and mouth disease virus (FMDV) is the cause of a widespread infectious disease affecting cloven-hoofed animals. It is controlled by vaccination with immune-inactivated virus grown in tissue culture. However, peptide vaccines represent a safer alternative to the current virus-inactivated immunogens. Their design requires the identification and evaluation of the sequences recognized by T- and B-lymphocytes. Four structural proteins, VP1, VP2, VP3, and VP4, comprise the viral capsid of the FMDV, but only VP1 has been extensively studied regarding the existence of relevant T-cell epitopes. Here, we utilize a murine model to present a functional T-cell epitope mapping on the complete sequences of VP2, VP3, and VP4 of FMDV O1 Campos. We used two in vitro assays to describe 13 amino acid sequences, each one of them including at least one T-cell epitope. The in vivo T-cell helper function of these sequences was studied in an adoptive cell-transfer assay in mice. Immunization experiments with a fusion peptide containing one of the sequences characterized were also done comparing the helper activity of this sequence with other T-cell epitopes included in the major immunogenic region of VP1.
Multiple sites of recombination within the RNA genome of foot-and-mouth disease virus.
Recombinant foot-and-mouth disease viruses were isolated from cells infected with a mixture of temperature-sensitive (ts) mutants belonging to different subtype strains. In order to select for recombination events in many different regions of the genome, crosses were performed between various pairs of mutants, with ts mutations in different regions of the genome. ts+ progeny were analysed by electrofocusing virus-induced proteins and RNase T1 fingerprinting of their RNA. All but 5 out of 43 independent isolates, from nine crosses, proved to have recombinant RNA genomes. Maps of these genomes, based on a knowledge of the locations of the unique oligonucleotides, were constructed. Most could be interpreted as being the products of single genetic cross-overs, although three recombinants were formed by two cross-overs each. Cross-overs in at least twelve distinct regions of the genome were identified. This evidence of a large number of recombination sites suggests that RNA recombination in picornaviruses is a general, as opposed to a site-specific, phenomenon.
Expression in Escherichia coli and purification of biologically active L proteinase of foot-and-mouth disease virus.
The foot-and-mouth disease virus (FMDV) Lb gene was cloned into bacterial expression vectors under the control of a T7 RNA polymerase promoter. The Lb protein was expressed in both an in vitro transcription-translation system and in Escherichia coli. In vitro expression of a construct containing the Lb gene fused to a portion of the VP4 and 3D genes demonstrated cis cleavage activity that could be blocked by the thiol protease inhibitor E-64. Lb expressed in E. coli was purified from the soluble fraction by metal chelation chromatography. Purified Lb had trans cleavage activity at the L/P1 junction and cleaved the p220 component of the cap-binding protein complex.
Characterization of an acid-resistant mutant of foot-and-mouth disease virus.
A foot-and-mouth disease virus mutant which is stable at pH 6.4 has been isolated from a virus of serotype A. In contrast to the parent (P) virus, which gave a mixture of large and small plaques in BHK21 cells and in a bovine kidney cell line, the acid-resistant (AR) virus gave small plaques which did not increase markedly in size after 24 hr. The infectivity titer of the acid-resistant virus was about 100-fold lower in suckling mice than in BHK21 cells, whether the inoculation was made intraperitoneally or intracerebrally, whereas the parent virus gave similar titers in both systems. Furthermore, in mice the AR virus reached its end point two to three times more slowly. The diameter of the AR virus was almost 20% less than that of the P virus and it had a more distinct topography, but the two viruses cosedimented in sucrose gradients. However, the buoyant density in CsCl of the AR virus was slightly lower (1.42 compared with 1.43 g/cc) in coruns. The RNAs and capsid proteins of the two viruses gave similar profiles in sucrose gradients and by SDS-PAGE, respectively. However, isoelectric focusing of the capsid proteins revealed considerable differences between the two viruses. Whereas the P virus gave four protein bands, corresponding to VP1-VP4, the AR virus gave one band for VP4, two for VP3, two for VP2, and four for VP1. Sequence analysis of the genes coding for the capsid protein regions of the two viruses showed four changes (one silent), resulting in an Ala-3-->Ser substitution in VP1 and Glu-131-->Lys and Asp-133-->Ser substitutions in VP2.
Evaluation of three 'ready to formulate' oil adjuvants for foot-and-mouth disease vaccine production.
Foot-and-mouth disease virus (FMDV) type OR(2)/75, grown on BHK 21 clone 13 cell monolayers, was inactivated with formalin. The virus was clarified and was either concentrated with 8% polyethylene glycol 6000 (PEG) or used in its untreated form for the preparation of oil adjuvant vaccines. The oil adjuvants used in this study were Montanide ISA 206 (which renders a water-in-oil-in-water (w/o/w) type of emulsion), Montanide ISA 57 and Montanide ISA 50V (both of which render water-in-oil (w/o) type of emulsions). The vaccines were tested on guinea pigs and calves. The results indicated that vaccines emulsified using Montanide ISA 57 elicited the best protective immune response in the animals, followed by those emulsified with Montanide ISA 50V and Montanide ISA 206. It was also found that vaccines formulated with virus concentrated using 8% polyethylene glycol (PEG) were more immunogenic than the vaccines formulated with the untreated harvest virus.
The sub-type classification of strains of foot-and-mouth disease virus.
Sixteen foot-and-mouth disease virus (FMDV) strains of type SAT 1 were compared in complement-fixation tests. With the test used, the range of antigenic variation within a type appeared to be greater than previously described. The concept of a sub-type group within which all strains are more closely related to each other than to any strain outside the group was not supported. Considering the group of strains studied, it is suggested that the classification of strains is best achieved by moninating a reference strain for each sub-type. Others are classified as related strains in one or more sub-type groups according to their relationships with the reference strains.
Recognition of the initiation codon for protein synthesis in foot-and-mouth disease virus RNA.
Foot-and-mouth disease virus (FMDV) RNA utilizes two in-frame initiation codons to produce two precursor proteins with identical carboxy termini. The 5' untranslated region (5'UTR) directs the ribosome to internal sequences without the need for a cap structure as used in host mRNAs. The FMDV 5'UTR was cloned upstream of the reporter gene chloramphenicol acetyltransferase (CAT) in order to study the selection of initiation site and to facilitate quantification of the translation products. After in vitro transcription with T7 RNA polymerase and translation in rabbit reticulocyte lysate, the two CAT products, resulting from initiation from the two initiation codons, were quantified. The downstream initiator AUG (AUGLb) was selected more efficiently in the wild-type 5'UTR. In truncated RNA, the upstream initiation site (AUGLab) was more efficiently utilized than in the wild-type 5'UTR. Protein synthesis initiation factors were added to translation assays to determine whether these factors influenced initiation site selection. Addition of eIF-2 and of eIF-2B changed the selection process for both types of RNA. These factors induced a 2.5-fold higher usage of the upstream AUGLab for wild-type and 5'UTR-truncated RNA. A change in mRNA concentration also induced a change in the usage of initiation codons; however, the effect of eIF-2 was measured over a broad range of mRNA concentrations. In conclusion, eIF-2 mediates the recognition of the initiation codon during both cap-dependent and internal ribosome entry site-dependent initiation.
Evidence for the role of His-142 of protein 1C in the acid-induced disassembly of foot-and-mouth disease virus capsids.
Foot-and-mouth disease virus (FMDV) capsids are inherently labile under mildly acidic conditions, dissociating to pentamers at pH values in the region of 6.5, with the release of protein 1A and the viral RNA. This acid-induced disassembly is thought to be required for the entry of the virus genome into the host cell. Previous work has highlighted a histidine-alpha-helix charge-dipole interaction at the twofold axes of symmetry between pentamers and has suggested that this interaction plays a role in acid-induced disassembly. The validity of this theory has now been tested by converting the implicated residue, His-142 of protein 1C, to Arg, Phe and Asp. The effects of such changes were studied by using a previously described vaccinia virus expression system, in which synthesis and processing of FMDV capsid proteins results in the self-assembly of capsids. In agreement with the histidine-alpha-helix charge-dipole theory, assembly in the arginine mutant was found to be greatly reduced, while capsids of the aspartic acid mutant were considerably more stable under acidic conditions than the wild-type. Aberrant but acid-stable complexes were obtained in the phenylalanine mutant.
Detergent-solubilized RNA polymerase from cells infected with foot-and-mouth disease virus.
The foot-and-mouth disease virus RNA polymerase complex was dissociated from cellular membranes with deoxycholate in the presence of dextran sulfate. The soluble polymerase complex was active in the cell-free synthesis of virus-specific RNA; solubilization of the complex permitted direct analysis of the cell-free reaction mixtures without recourse to RNA extraction. A major RNA-containing component found early during cell-free incubation ranged from approximately 140 to 300S. The final major products of the cell-free system were 37S virus RNA, 20S ribonuclease-resistant RNA, and a 50S component containing RNA.
Viral RNA modulates the acid sensitivity of foot-and-mouth disease virus capsids.
Foot-and-mouth disease virus (FMDV) manifests an extreme sensitivity to acid, which is thought to be important for entry of the RNA genome into the cell. We have compared the low-pH-induced disassembly in vitro of virions and natural empty capsids of three subtypes of serotype A FMDV by enzyme-linked immunosorbent assay and sucrose gradient sedimentation analysis. For all three subtypes (A22 Iraq 24/64, A10(61), and A24 Cruzeiro), the empty capsid was more stable by 0.5 pH unit on average than the corresponding virion. Unexpectedly, in the natural empty capsids used in this study, the precursor capsid protein VP0 was found largely to be cleaved into VP2 and VP4. For picornaviruses the processing of VP0 is closely associated with encapsidation of viral RNA, which is considered likely to play a catalytic role in the cleavage. Investigation of the cleavage of VP0 in natural empty capsids failed to implicate the viral RNA. However, it remains possible that these particles arise from abortive attempts to encapsidate RNA. Empty capsids expressed from a vaccinia virus recombinant showed essentially the same acid lability as natural empty capsids, despite differing considerably in the extent of VP0 processing, with the synthetic particles containing almost exclusively uncleaved VP0. These results indicate that it is the viral RNA that modulates acid lability in FMDV. In all cases the capsids dissociate at low pH directly into pentameric subunits. Comparison of the three viruses indicates that FMDV A22 Iraq is about 0.5 pH unit more sensitive to low pH than types A10(61) and A24 Cruzeiro. Sequence analysis of the three subtypes identified several differences at the interface between pentamers and highlighted a His-alpha-helix dipole interaction which spans the pentamer interface and appears likely to influence the acid lability of the virus.
Identification of the active-site residues of the L proteinase of foot-and-mouth disease virus.
The foot-and-mouth disease virus (FMDV) leader (L) protein is involved in autocatalytic cleavage at the L/P1 junction and in the cleavage of translation initiation factor p220, a subunit of the cap-binding protein complex. It has been suggested that this proteinase has homology to the papain-like family of cysteine proteinases, and from this information, we have investigated the active-site residues by introducing specific mutations into the L gene. Mutations of Cys-23 to Ala or His-120 to Leu resulted in enzymes that lacked cis activity at the L/VP4 cleavage site, trans activity on a truncated L-P1 substrate, and p220 cleavage activity. Mutations of Cys-23 to ser or His-110 to Leu resulted in enzymes that retained some or all cis activity and had reduced p220 cleavage. These mutations were introduced separately into a full-length FMDV cDNA, and RNA transcripts derived from these cDNAs were translated in a cell-free system and transfected into cells. The C23S mutant inefficiently cleaved at the L/P1 junction and within P1, and virus obtained from transfected cells reverted to wild type. The H110L mutant cleaved the L/P1 junction almost as well as the wild-type enzyme, and virus recovered from transfected cells retained the mutation and displayed wild-type viral protein synthesis and host shut-off kinetics.
Cross-reactive idiotopes among anti-foot and mouth disease virus neutralizing antibodies.
Foot and mouth disease virus (FMDV) viral protein 1 is the only one of the four viral proteins (VP) that induces neutralizing antibodies as an isolated protein. A 32 amino acid (AA) residue (32dimer) of FMDV subtype A12 Lp ab VP1 (AA 137-168) was immunogenic against the A12 subtype. Three antibody populations each recognizing different epitopes on 32dimer were isolated by affinity chromatography (AFC) from the serum of a steer which had been immunized with the 32dimer. The 32dimer contains an AA sequence that is recognized by a protective paratope carried on a murine monoclonal antibody (mAb) (7SF-3.H3.1). Polyclonal anti-7SF-3 idiotype antibodies specifically inhibited the binding activity of one of these anti-32dimer antibody populations suggesting the existence of cross-reactive paratopic-related idiotopes between mAb 7SF-3 and antibodies elicited by the 32dimer. These anti-idiotypic antibodies were used in AFC to purify antibodies from the anti-32dimer serum. The purified antibody population has characteristics that resemble those of the mAb 7SF-3, i.e. its reactivity with FMDV A subtypes in ELISA, radioimmunoassay (RIA), mouse neutralization and its lack of reactivity with a mAb 7SF-3 neutralizing escape virus variant. Furthermore, these antibodies were specifically inhibited by either anti-mAb 7SF-3 idiotypic antibodies or peptides containing the mAb 7SF-3 epitope. Using the same experimental approach, mAb 7SF-3 idiotope-bearing antibodies were shown to be present in serum from bovine and swine convalescent from FMDV A12 Lp ab infection. Thus, the highly immunogenic area between residues 137 and 168 of FMDV VP1 elicited a cross-reactive neutralizing idiotope response conserved amongst several animal species.
[Establishment of a relation between the variations of the properties of foot and mouth disease virus cultured on elective embryoma, and the stages of clinical evolution of the foot and mouth disease; individualization of the optimum stage for the preparation of vaccines].
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[Behavior of foot and mouth disease virus for adsorption in aluminum hydroxide and subsequent elution. III. Purification and concentration of foot and mouth disease virus through aluminum hydroxide].
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