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PubMed2000

Type I interferon production in cattle infected with 2 strains of foot-and-mouth disease virus, as determined by in situ hybridization.

Four calves were exposed via aerosol to 1 of 2 strains of foot-and-mouth disease virus. Two animals received virus derived from an infectious clone virus (A12-IC) and 2 received virus derived from the same clone but which lacked the leader coding region (A12-LLV2) that codes for a protein responsible for turning off host protein synthesis. Animals were euthanized at 24 and 72 h post exposure. Cattle receiving A12-IC had a rapid course of disease with more virus in tissues while A12-LLV2-infected cattle did not develop clinical signs of disease. Formalin-fixed, paraffin-embedded tissue sections were probed with digoxigenin-labeled riboprobes corresponding to the coding sequence for bovine interferon (IFN) alpha and IFNbeta. Staining for IFNalpha mRNA was noted in mononuclear cells of the lungs of all animals and in respiratory lymph nodes of cattle receiving A12-IC. Staining for IFNbeta mRNA was confined to bronchiolar epithelium and present only in the animals infected with A12-IC. Inability of the A12-LLV2 virus to achieve levels of spread seen with A12-IC may be related to translation of IFNalpha in A12-LLV2-infected cells, which renders adjacent cells less susceptible to productive infection.

Animals↗
PubMed2006

Plus- and minus-stranded foot-and-mouth disease virus RNA quantified simultaneously using a novel real-time RT-PCR.

Even though tagged RT-PCR and rTth RT-PCR have been developed to improve strand-specific detection of RNA virus, these assays are not quantitative. In this study, a novel real-time RT-PCR assay, which combines the benefits of both the tagged and rTth RT-PCR has been developed to quantify the strand-specific RNA of foot-and-mouth disease virus (FMDV). The tagged-primers plus a TaqMan probe located within the highly conserved viral 3D region were used. The in vitro synthesized minus-and plus-stranded RNA templates were used as a dual control along with the copy number of viral RNA molecules, which is more reliable than reported RT-PCR employing a DNA-based standard. This assay was used to quantify FMDV RNA from 10(9) to 10(1) copies with a maximum sensitivity of between ten and five copies and was shown to be highly reproducible with low intra-and inter-assay variation. Coefficients of variation (CV) values were 0.70-1.39% and 0.98-2.1%, respectively. Importantly, the method was applied to simultaneously quantify both plus-stranded and minus-stranded FMDV RNA using tagged-RT and tagged-FP primer during a high-temperature reverse transcription. Highly sensitive and strand-specific real-time RT-PCR assay has been established. We tested the ratio of viral plus-stranded to minus-stranded RNA in acutely infected and persistently infected BHK-21 cells, for which the values ranged from 22/1 to 143/1 and from 287/1 to 334/1, respectively, suggesting different replication patterns of plus-and minus-stranded RNA in acutely infected and persistently infected cells. This value ranged from 83/1 to 93/1 in enriched FMDV virions, indicating that FMDV encapsidation is highly specific for plus-stranded RNAs. In addition, the method was applied to surveille the FMDV replication at animal level.

Animals↗
PubMed1997

Antigenic features of foot-and-mouth disease virus serotype Asia1 as revealed by monoclonal antibodies and neutralization-escape mutants.

Neutralizable antigenic sites/epitopes of serotype Asial foot-and-mouth disease virus (strain IND63/72) were identified using monoclonal antibodies (mabs) and their neutralization-escape mutants. Relative affinity/reactivity of the mabs for viral (both native and trypsin-cleaved) and subviral antigens in enzyme-linked immunosorbent assay (ELISA) showed dominance of trypsin-sensitive and conformation-dependent neutralizable antigenic sites. Characterization of neutralization escape mutants identified at least four independent trypsin-sensitive neutralizable antigenic sites on Asial FMD virus. One site was identified by mabs B3, 1A, 24, 2A, 40 and 63, second site by mabs 34 and 81, third site by mab 72 and fourth site by mab 89. The reaction profile of the mabs with selected field isolates in ELISA identified four different neutralization epitopes within the site B3/1A/24/2A/40/63.

Animals↗
PubMed2004

Foot-and-mouth disease polyvalent oil vaccines inoculated repeteadly in cattle do not induce detectable antibodies to non-structural proteins when evaluated by various assays.

The use of foot-and-mouth disease (FMD) vaccines that do not induce antibodies against non-structural proteins (NSP) is extremely relevant for the demonstration of regions "free of FMDV infection" and control strategies. In this study cattle were primed and boosted with five doses of oil vaccines containing high antigenic payloads on days 0, 90, 130, 160 and 200. The serological response against NSP was measured using four commercially available assays: two 3ABC-ELISAs; one 3B-ELISA (and complementary 3A-ELISA) and an enzyme-immunotransfer blot assay (EITB). Additionally, locally produced NSP antibodies detection reagents and VIAA antibodies were evaluated. A high level of specific immune response against vaccine strains was shown. After four doses of vaccine, non-reactive animals were detected by any of the NSP assays. After the fifth immunization, 2 of 17 animals were reactive in one ELISA kit, but these samples proved negative by confirmatory tests. Antibodies against NSP were not detected in single dose immunized cattle. The principle of the NSP-ELISA used as a screening test for large sero-surveys in South America is established and this paper emphasizes the importance of using vaccines that have demonstrated no interference with NSP antibodies detection assays.

Animals↗
PubMed1994

Genetic relationships between foot-and-mouth disease type Asia 1 viruses.

The sequence of 165 nucleotides at the 3' end of the 1D (VP1) gene of foot-and-mouth disease (FMD) virus was determined for 44 type Asia 1 strains isolated from throughout Asia between 1954-92. Analysis of the relationships between the virus genomes showed epidemiological links not previously evident. The possible origin of the only outbreak of FMD Asia 1 to have occurred in Europe, in Greece in 1984, was identified because the nucleotide sequence of this virus was closely-related to the sequences of those present in the Middle East between 1983-5. Variation in the region sequenced was not as great as that seen in the other FMDV serotypes and all viruses shared greater than 85% nucleotide identity. Thus all the virus isolates examined were considered to belong to a single genotype. A database of Asia 1 virus sequences has been established which will facilitate the rapid analysis of new outbreaks strains.

Amino Acid Sequence↗
PubMed2004

High-level expression of codon optimized foot-and-mouth disease virus complex epitopes and cholera toxin B subunit chimera in Hansenula polymorpha.

A codon optimized DNA sequence coding for foot-and-mouth disease virus (FMDV) capsid protein complex epitopes of VP1 amino acid residues 21-40, 135-160, and 200-213 was genetically fused to the N-terminal end of a 6x His-tagged cholera toxin B subunit (CTB) gene with the similar synonymous codons preferred by the methylotropic yeast Hansenula polymorpha. The fusion gene was synthesized based on a polymerase chain reaction (PCR) and subsequently overexpressed in H. polymorpha. The chimeric protein was successfully secreted into the culture medium (up to 100mg/L) and retained the antigenicity associated with CTB and FMDV antibodies by Western blot analysis. The chimera after purification through Co(2+)-charged resin column bound specifically to GM1 ganglioside receptor and thus retained the biological activity of CTB. This study has important implications in the construction of CTB chimera for mucosal vaccines against FMDV.

Base Sequence↗
PubMed1992

Primer design for specific diagnosis by PCR of highly variable RNA viruses: typing of foot-and-mouth disease virus.

A PCR assay for the specific detection and identification of viral sequences that correlate with established serotypes of foot-and-mouth disease virus (FMDV) has been developed. A new analysis based on homology profiles among reported sequences was used for primer design. RNA replicase (3D) gene regions that showed high homology among FMDVs, and low homology to other picornaviruses, were used for PCR amplification. Specific and highly sensitive detection was achieved for RNA of FMDV types C, A, and O, either purified or extracted from vesicular fluids of infected animals, under reaction conditions permissive for the detection of variants present in the virus population. Similarly, serotype-specific primers were designed to amplify the carboxy-terminal end of VP1 gene of FMDV types either C, A, or O. The results of PCR amplification of 15 different FMDV RNAs using type-specific primers are in agreement with the serological typing of the corresponding viruses and show that the primer-selection procedure developed for FMDV constitutes a reliable method of viral diagnosis.

Animals↗
PubMed2006

Structural and mutagenic analysis of foot-and-mouth disease virus 3C protease reveals the role of the beta-ribbon in proteolysis.

The 3C protease (3C(pro)) from foot-and-mouth disease virus (FMDV), the causative agent of a widespread and economically devastating disease of domestic livestock, is a potential target for antiviral drug design. We have determined the structure of a new crystal form of FMDV 3C(pro), a chymotrypsin-like cysteine protease, which reveals features that are important for catalytic activity. In particular, we show that a surface loop which was disordered in previous structures adopts a beta-ribbon structure that is conformationally similar to equivalent regions on other picornaviral 3C proteases and some serine proteases. This beta-ribbon folds over the peptide binding cleft and clearly contributes to substrate recognition. Replacement of Cys142 at the tip of the beta-ribbon with different amino acids has a significant impact on enzyme activity and shows that higher activity is obtained with more hydrophobic side chains. Comparison of the structure of FMDV 3C(pro) with homologous enzyme-peptide complexes suggests that this correlation arises because the side chain of Cys142 contacts the hydrophobic portions of the P2 and P4 residues in the peptide substrate. Collectively, these findings provide compelling evidence for the role of the beta-ribbon in catalytic activity and provide valuable insights for the design of FMDV 3C(pro) inhibitors.

3C Viral Proteases↗
PubMed1978

Inactivated-concentrated virus antigen for indirect complement fixation test of foot-and-mouth disease.

To the culture fluids of BHK-21 cells infected with each of types O, A, and Asia 1 of foot-and-mouth disease virus was added acetylethyleneimine to 0.05% (v/v). The mixtures were incubated at 37 degrees C for 24 hours. To them were then added polyethylene glycol 6000 to 10% (w/v), and the mixtures concentrated to one-tenth of the initial volume. The resulting inactivated-concentrated virus antigens showed a complement fixation (CF) titer ranging from 12 to 24. The recovery rate of CF activity was 40 approximately 60%. This activity of each antigen was maintained at 4 degrees C or -70 degrees C for 6 months at least. Experimentally infected cattle were examined for the development of antibody by the aid of the indirect complement fixation (ICF) test with those antigens. As a result, ICF antibody began to be detected 3 approximately 5 days after inoculation. Its titer reached a maximum 10 approximately 14 days after inoculation and decreased gradually thereafter. It was detected even 232 days after inoculation. There was a tendency for the development of ICF antibody to be parallel with that of neutralizing antibody. It was suggested that ICF antibody might be type-specific. In conclusion, the antigens prepared had such high activity that they could be used for the determination of antibody by ICF. In addition, they were of great practical value because of their sufficient keeping quality and safety.

Animals↗
PubMed2005

Secretory IgA as an indicator of oro-pharyngeal foot-and-mouth disease virus replication and as a tool for post vaccination surveillance.

A serotype-specific ELISA was developed to detect foot-and-mouth disease virus (FMDV) specific IgA antibody in the saliva of cattle, and the method was evaluated for its feasibility in detecting serotype O FMDV carrier animals, particularly amongst vaccinated cattle that had subsequently become sub-clinically infected. For this purpose, saliva samples were collected from naïve cattle (n = 173), FMDV challenged cattle (n = 10), FMDV vaccinated cattle (n = 40) and FMDV vaccinated-and-challenged cattle (n = 40). A subset of 29 cattle was sampled for 105-168 days after challenge. The FMDV infection status of each of the cattle was determined by virus isolation and RT-PCR tests on oesophago-pharyngeal fluids and the ability of the IgA test to detect viral infection and persistence was compared to an ELISA for the detection of serum antibodies against the 3ABC non-structural proteins of FMDV. Eleven out of twelve vaccinated cattle that were shown to be persistently infected with FMDV up to or beyond 28 days post challenge, were also detected by the IgA test on saliva. With some modification and further validation, this test could be useful in post-vaccination surveillance to help confirm the absence of sub-clinical infection in order to regain the FMD-free status of a region or country.

Animals↗
PubMed1996

Persistent infection of African buffalo (Syncerus caffer) with SAT-type foot-and-mouth disease viruses: rate of fixation of mutations, antigenic change and interspecies transmission.

Transmission of a plaque-purified SAT-2 foot-and-mouth disease virus (FMDV) occurred erratically from artificially infected African buffaloes in captivity to susceptible buffaloes and cattle in the same enclosure; in some instances transmission occurred only after contact between persistently infected carriers and susceptible animals lasting a number of months. Because the rate at which FMDV mutations accumulated in persistently infected buffaloes was approximately linear (1.64 percent nucleotide substitutions per year over the region of the 1D gene sequenced), both buffaloes and cattle that became infected some months after the start of the experiment were infected with viruses that differed from the original clone. The nucleotide differences were reflected in significant antigenic change. A SAT-1 FMDV from a separate experiment inadvertently infected some of the buffalo in the SAT-2 experiment. The SAT-1 FMDV also accumulated mutations at a constant rate in individual buffaloes (1.54 percent nucleotide changes per year) but the resultant antigenic variation was less than for SAT-2. It is concluded that persistently infected buffaloes in the wild constantly generate variants of SAT-1 and SAT-2 which explains the wide range of genomic and antigenic variants which occur in SAT-1 and SAT-2 viruses in southern Africa.

Amino Acid Sequence↗
PubMed2006

Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe.

The nucleoside analogue ribavirin (R) is mutagenic for foot-and-mouth disease virus (FMDV). Passage of FMDV in the presence of increasing concentrations of R resulted in the selection of FMDV with the amino acid substitution M296I in the viral polymerase (3D). Measurements of progeny production and viral fitness with chimeric viruses in the presence and absence of R documented that the 3D substitution M296I conferred on FMDV a selective replicative advantage in the presence of R but not in the absence of R. In polymerization assays, a purified mutant polymerase with I296 showed a decreased capacity to use ribavirin triphosphate as a substrate in the place of GTP and ATP, compared with the wild-type enzyme. The results suggest that M296I has been selected because it attenuates the mutagenic activity of R with FMDV. Replacement M296I is located within a highly conserved stretch in picornaviral polymerases which includes residues that interact with the template-primer complex and probably also with the incoming nucleotide, according to the three-dimensional structure of FMDV 3D. Given that a 3D substitution, distant from M296I, was associated with resistance to R in poliovirus, the results indicate that picornaviral polymerases include different domains that can alter the interaction of the enzyme with mutagenic nucleoside analogues. Implications for lethal mutagenesis are discussed.

Amino Acid Substitution↗
PubMed1995

Foot-and-mouth disease virus undergoes restricted replication in macrophage cell cultures following Fc receptor-mediated adsorption.

We have previously reported that foot-and-mouth disease virus (FMDV) can enter an Fc receptor (FcR)-expressing cell line by antibody-dependent enhancement. Since FMDV can establish a persistent infection in animals in the presence of high levels of neutralizing antibodies (carrier state), we examined macrophages for their ability to be infected by the virus in the presence of antibody. The murine macrophage cell line P388D1 or porcine macrophage-monocytes isolated from peripheral blood were incubated with antibody-complexed virus. Under these conditions, host protein synthesis was rapidly inhibited in both cell types, but not in cells incubated either with virus alone or with imine-inactivated antibody-complexed virus. Virus-specific structural and nonstructural proteins were synthesized in antibody-complexed virus-infected P388D1 cells, while only nonstructural proteins were detected in porcine macrophage cultures. Negative-strand RNAs were detected in both cell types, indicating that RNA replication had taken place. Cultures of P388D1 cells transfected with viral RNA produced very low levels of infectious virus, and infection with virus-antibody complexes, followed by a brief wash with pH 6.0 buffer to remove residual input virus, allowed the detection of low levels of productive replication. Thus, macrophages can be infected with FMDV via FcR-mediated adsorption, and infection of these cells could contribute to pathology or provide a reservoir of infectious virus in carrier animals.

Adsorption↗
PubMed2004

Foot-and-mouth disease virus leader proteinase: specificity at the P2 and P3 positions and comparison with other papain-like enzymes.

The foot-and-mouth disease virus Leader proteinase (L(pro)) frees itself from the growing viral polyprotein by self-processing between its own C-terminus and the N-terminus of the subsequent protein VP4. The ArgLysLeuLys*GlyAlaGlyGln sequence is recognized. The proteinase subsequently cleaves the two isoforms of host cell protein eukaryotic initiation factor (eIF) 4G at the AlaAsnLeuGly*ArgThrThrLeu (eIF4GI) and LeuAsnValGly*SerArgArgSer (eIF4GII) sequences. The enzyme does not, however, recognize the sequence on eIF4GII (AlaAspPheGly*ArgGlnThrPro) which is analogous to that recognized on eIF4GI. To investigate the basis for this specificity, we used site-directed mutagenesis to show that the presence of Phe at the P2 position or Asp at the P3 position severely compromises self-processing. Furthermore, these substitutions also give rise to the production of aberrant cleavage products. As Leu is the preferred amino acid at P2, the specificity of L(pro) is reminiscent of that of cathepsin K. This cellular proteinase can also process collagen through its ability to accept proline at the P2 position. Investigation of the L(pro) substrate specificity showed, however, that in contrast to cathepsin K, L(pro) cannot accept Pro at P2 and does not cleave collagen. Subtle variations in the arrangement of the S2 binding pockets on the enzymes are responsible for these differences in specificity.

Amino Acid Substitution↗
PubMed1996

Recognition of foot-and-mouth disease virus and its capsid protein VP1 by bovine peripheral T lymphocytes.

The role of T cells in immunity to foot-and-mouth disease virus is still poorly defined compared to that of the humoral response. In this paper we describe a systematic, longitudinal study on the cellular recognition of FMDV and its subunit protein VP1 by bovine peripheral blood T lymphocytes. Multiple vaccination with a single virus serotype induced a serotype cross-reactive proliferative T cell repertoire that varied in magnitude between individual animals and with the serotype of the vaccine used. Primary proliferative T cell responses of vaccinated and acutely infected cattle were weak relative to the magnitude of responses determined for the same animals after boosting. In contrast, the level of circulating antibody produced after both primary and secondary exposure to virus was good. Phenotypic analysis of lymphocytes from vaccinated or infected cattle showed a small increase in CD8+ T cells after infection compared to vaccination. However, in general the profiles of circulating lymphocytes elicited were similar. Thus, we were not able to use proliferative or phenotypic analyses to distinguish between vaccinated and convalescent cattle. T cell recognition of VP1 by multiply-vaccinated cattle was serotype-specific implying that the cross-reactive responses observed with whole virus may be attributed to proteins other than VP1. In contrast to other studies, immunization with recombinant VP1 induced only low levels of neutralizing antibody and failed to elicit profound proliferative responses or protection ever after two immunizations.

Animals↗
PubMed1999

Monoclonal antibodies to an Indian strain of type A foot-and-mouth disease virus.

A set of five neutralizing monoclonal antibodies (MAbs) to an Indian strain (IND17/77) of type A (subtype A22) foot-and-mouth disease (FMD) virus (FMDV) was used in the study. Four of the MAbs (27S, 37S, 85S, and 143S) identified a trypsin-sensitive (TS) epitope(s) and were specific for VP1, while the remaining MAb (145S) reacted with a trypsin-resistant (TR) epitope and was specific for VP3 in Western blot analysis. Both the epitopes (TS and TR) were conformation-independent in nature. Results obtained in MAb-competition enzyme-linked immunosorbent assay (ELISA), and profiling of the (MAb) neutralization-escape mutants in ELISA and cross-neutralization test revealed two overlapping TS epitopes (27S/37S and 85S/143S) on the virus. Variation at both these epitopes was observed in some field isolates of serotype A. Comparison of deduced amino acid sequence in the VP1 region (aa 140-213) between the parent virus and the mutants identified Gly148 and Arg153 as critical for the formation of both the TS epitopes. Substitution of R153 by Gly or Ser was observed in mutants with no reactivity for the MAbs 85S/143S. However, these mutants maintained partial reactivity with MAbs 27S/37S, and substitution of Gly148 by Glu eliminated both the epitopes. No amino acid substitution was observed in the VP1 region of aa 200-213. Efficient neutralization of the MAb neutralization escape mutants (MAb-resistant (MAR) mutants) by bovine vaccinate serum (BVS) indicated involvement of other epitopes on the virion surface in eliciting neutralizing antibodies following vaccination.

Amino Acid Substitution↗
PubMed1969

Immunochemical studies of foot-and-mouth disease. V. Antigenic variants of virus demonstrated by immunodiffusion analyses with 19S but not 7S antibodies.

Three antigenic variants of foot-and-mouth disease virus, type A, strain 119, were demonstrated in Ouchterlony analyses utilizing serum collected from guinea pigs 7 days postinfection (DPI). Such antisera contain antibodies of the 19S class. Guinea pig antisera that contained antibodies of the 7S class were unable to distinguish between the antigenic variants. Similarly, 19S antibody was able to demonstrate antigenic differences in trypsin- and chymotrypsin-treated viruses that were not detected by 7S antibody-containing antisera. One of the antigenic variants of virus is apparently the wild type and is tentatively considered to have two antigenic determinant groupings termed the a- and b-sites (140S-ab). The 140S-ab variant was the sole or predominant antigenic type produced in guinea pigs and in large plaque-forming- and tissue culture-low passage sources of the virus. Another antigenic variant appears to possess only the b-site (140S-b) and was the major constituent in tissue culture-high passage virus preparations. The third variant, a small plaque former, was also devoid of the a-site and contains an antigenic determinant that is related to, but not identical with, the b-site. This variant appears to be a minor constituent of tissue culture-high passage virus. 7-DPI serum could be absorbed with a suitable concentration of tissue culture-high passage virus to remove antibody reactive with the b-determinant site. This absorbed serum still precipitated 140S-ab virus by virtue of still containing antibody reactive with the a-determinant site; however, the neutralizing activity was eliminated. This suggests that the b-site is critical with respect to neutralization while the a-site is noncritical.

Animals↗