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The genome-linked protein of foot-and-mouth disease virus was examined by electrofocusing in polyacrylamide gels. Two proteins of different charge and amino acid composition were found. The tryptic peptide maps of the proteins were dissimilar. The possible relationship between the two proteins is discussed.
Hypervirulent variants of foot-and-mouth disease virus (FMDV) of serotype C arise upon serial cytolytic or persistent infections in cell culture. A specific mutation in the internal ribosome entry site of persistent FMDV was previously associated with enhanced translation initiation activity that could contribute to the hypervirulent phenotype for BHK-21 cells. Here we report that several hypervirulent FMDV variants arising upon serial cytolytic passage show an invariant internal ribosome entry site but have a number of mutations affecting structural and nonstructural viral proteins. The construction of chimeric type O-type C infectious transcripts has allowed the mapping of a major determinant of hypervirulence to the viral capsid. Tissue culture-adapted FMDV displayed enhanced affinity for heparin, but binding to cell surface heparan sulfate moieties was not required for expression of the hypervirulent phenotype in Chinese hamster ovary (CHO) cells. Virulence was identical or even higher for glycosaminoglycan-deficient CHO cells than for wild-type CHO cells. FMDV variants with decreased affinity for heparin were selected from a high-binding parental population and analyzed. Substitutions associated with decreased heparin binding were located at positions 173 of capsid protein VP3 and 144 of capsid protein VP1. These substitutions had a moderate effect on virulence for BHK-21 cells but completely abrogated infection of CHO cells. The comparative results with several FMDV isolates show that (i) increased affinity for heparin and alterations in cell tropism may be mediated by a number of independent sites on the viral capsid and (ii) the same capsid modifications may have different effects on different cell types.
Porcine T-cell recognition of foot-and-mouth disease virus (FMDV) nonstructural proteins (NSP) was tested using in vitro lymphoproliferative responses. Lymphocytes were obtained from outbred pigs experimentally infected with FMDV. Of the different NSP, polypeptides 3A, 3B, and 3C gave the highest stimulations in the in vitro assays. The use of overlapping synthetic peptides allowed the identification of amino acid regions within these proteins that were efficiently recognized by the lymphocytes. The sequences of some of these antigenic peptides were highly conserved among different FMDV serotypes. They elicited major histocompatibility complex-restricted responses with lymphocytes from pigs infected with either a type C virus or reinfected with a heterologous FMDV. A tandem peptide containing the T-cell peptide 3A[21-35] and the B-cell antigenic site VP1[137-156] also efficiently stimulated lymphocytes from infected animals in vitro. Furthermore, this tandem peptide elicited significant levels of serotype-specific antiviral activity, a result consistent with the induction of anti-FMDV antibodies. Thus, inclusion in the peptide formulation of a T-cell epitope derived from the NSP 3A possessing the capacity to induce T helper activity can allow cooperative induction of anti-FMDV antibodies by B cells.
Typing of foot-and-mouth disease (FMD) virus was performed by the direct fluorescent antibody (FA) technique. Type-specific FA was prepared from the following two sorts of procedures: (1) FA against live virus (FA-live) was prepared from hyperimmune serum taken from guinea pigs having received live FMD virus. Then it was adsorbed with concentrated heterotype antigen. (2) FA against inactivated virus (FA-Inact) was prepared from antiserum taken from guinea pigs immunized with purified FMD virus inactivated with acetylethyleneimine. Seventeen strains of FMD virus (seven strains of type A, seven strains of type O, and three strains of thpe C) were used. Type-specific FMD virus antigen was detected distinctly from the monolayer of BHK cells infected with each type of virus and fixed in acetone, in spite of negative results obtained from the cells fixed in methyl alcohol. All the 17 strains were typed successfully by the implementation of these two FA methods.
Field strains of foot-and-mouth disease (FMD) virus which differ immunogenically from vaccine strains appear from time to time and may present serious problems for FMD campaigns. In order that appropriate measures can be taken it is important to determine the degree of differences between the vaccine strain and the variant strain soon after its appearance. With the A strains studied it was observed that a serological relationship by complement fixation test of greater than or equal to 0.40 would indicate sufficient protection of the vaccine strain for the field strain. With a lower relationship, however, the vaccine strains usually do not fully protect against the field strain. The mouse protection test can be used to determine how serious the lack of protection may be. With this test routine it is possible to issue alerts for intensified epidemiological surveillance within 2-3 weeks after the field strain is received at the Center.
The numbers of plaques produced by foot-and-mouth disease virus in primary cultures of calf kidney cells conditioned to 24, 30, and 37 C were essentially the same if virus was absorbed at 37 C. Adsorption was as effective at 30 as at 37 C in cultures conditioned to the respective temperature, but 24 C was less effective under this condition. However, when the adsorption temperature for cultures conditioned to 37 C was decreased to 30 or 24 C, fewer plaques were produced than in cultures conditioned to and maintained at the lower temperatures during absorption. Comparison of the number of plaques produced in cultures overlaid with nutrient agar containing from 0.5 to 10% bovine serum revealed no difference in relation to serum concentration. However, plaque size was related directly to the concentration of serum in the overlay.
A method of negative staining of foot-and-mouth disease virus preparations permits to obtain separately positive (2% phosphotungstic acid solution, pH 3.0) and negative (2% PTA solution, pH 6.8 +/- 8.0) stainings. When a 3--4% PTA solution, pH 6.8 +/- 8.0 is used, simultaneous positive and negative staining of each virion is possible which characterizes the functional heterogeneity of the virion protein membrane in interaction with PTA anions.
The antibody response to foot-and-mouth disease virus (FMDV) antigens of type Asia-1 in guinea-pigs was studied by micro-serum neutralization test (MSNT) and enzyme-linked immunosorbent assay (ELISA). One inoculation of as little as 1 microgram of binary ethyleneimine (BEI)-inactivated 146S virus particles in guinea-pigs elicited enough neutralizing antibodies to protect them against challenge with virulent virus. However, one inoculation of live 146S virus particles elicited higher levels of neutralizing antibodies in guinea-pigs than that of inactivated 146S particles. One inoculation of 12S protein subunits in guinea-pigs elicited only non-neutralizing anti-12S antibodies detected by ELISA. Similarly, non-neutralizing anti-VP1 antibodies were detected by ELISA after one inoculation of VP1. However, multiple inoculations of 12S or VP1 elicited measurable neutralizing antibodies in guinea-pigs that protected them against challenge.
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Foot-and-mouth disease virus (FMDV) binds to cellular integrins through an RGD motif in its capsid protein, VP1. It is unclear, however, what kind of cellular event(s) are triggered after the binding of VP1 to the cells. In this study, we show that aqueous soluble recombinant DNA-derived VP1 (rVP1) of FMDV induced apoptosis of BHK-21 cells after binding to integrins. In addition, treatment of BHK-21 cells with rVP1 resulted in deactivation of Akt and enhancement of several proapoptotic responses such as dephosphorylation of glycogen synthase kinase-3beta and cleavage of procaspase-3, -7, and -9. Additional studies revealed that the rVP1 treatment caused apoptosis of cancer cells, including MCF-7 (a breast carcinoma cell line with a functional deletion of the caspase-3 gene) and PC-3 (a sphingosine 1-phosphate receptor subtype 3-deficient androgen-independent prostate cancer cell line). These results suggest that rVP1 of FMDV may be used selectively as a potent apoptotic agent for human cancer by modulating the Akt signaling pathway and that its effect is not primarily dependent on either activation of procaspase-3 or deactivation of sphingosine 1-phosphate receptor subtype 3.
Foot-and-mouth disease virus (FMDV) enters cells by attaching to cellular receptor molecules of the integrin family, one of which has been identified as the RGD-binding integrin alpha(v)beta3. Here we report that, in addition to an integrin binding site, type O strains of FMDV share with natural ligands of alpha(v)beta3 (i.e., vitronectin and fibronectin) a specific affinity for heparin and that binding to the cellular form of this sulfated glycan, heparan sulfate, is required for efficient infection of cells in culture. Binding of the virus to paraformaldehyde-fixed cells was powerfully inhibited by agents such as heparin, that compete with heparan sulfate or by agents that compete for heparan sulfate (platelet factor 4) or that inactivate it (heparinase). Neither chondroitin sulfate, a structurally related component of the extracellular matrix, nor dextran sulfate appreciably inhibited binding. The functional importance of heparan sulfate binding was demonstrated by the facts that (i) infection of live cells by FMDV could also be blocked specifically by heparin, albeit at a much higher concentration of inhibitor; (ii) pretreatment of cells with heparinase reduced the number of plaques formed compared with that for untreated cells; and (iii) mutant cell lines deficient in heparan sulfate expression were unable to support plaque formation by FMDV, even though they remained equally susceptible to another picornavirus, bovine enterovirus. The results show that entry of type O FMDV into cells is a complex process and suggest that the initial contact with the cell surface is made through heparan sulfate.
Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals. For several years, vaccination of animals, which had proven to be successful for the eradication of the disease, has been forbidden in the United States and the European Community because of the difficulty of differentiating between vaccinated and infected animals. In this study, detailed investigations of the bovine humoral immune response against FMD virus (FMDV) were performed with the aim of identifying viral epitopes recognized specifically by sera derived from FMDV-infected animals. The use of overlapping 15-mer synthetic peptides, covering the whole open reading frame of FMDV strain O(1)K in a peptide enzyme-linked immunosorbent assay, allowed the identification of 12 FMDV strain O(1)K-specific linear B-cell epitopes. Six of these linear B-cell epitopes, located in the nonstructural proteins, were used in further assays to compare the reactivities of sera from vaccinated and infected cattle. Antibodies recognizing these peptides could be detected only in sera derived from infected cattle. In further experiments, the reactivity of the six peptides with sera from animals infected with different strains of FMDV was tested, and strain-independent infection-specific epitopes were identified. Thus, these results clearly demonstrate the ability of a simple peptide-based assay to discriminate between infected and conventionally FMD-vaccinated animals.
As a highly contagious disease in cloven-hoofed animals, foot-and-mouth disease virus (FMDV) may cause a considerable social-economic loss in those countries affected. IFN-gamma has a wide range of antiviral and immune modulating functions. Thus, to study the immune enhancing effects of recombinant Bovine IFN-gamma (rBoIFN-gamma) on a recombinant FMDV vaccine, BoIFN-gamma, FMDV VP1 and BoIFN-gamma/VP fusion genes were cloned, expressed, co-expressed in pichia pastoris (P. pastoris) respectively, and subsequent immune effects have been evaluated in this study. The results showed that the genes encoding for BoIFN-gamma, VP1 and BoIFN-gamma/VP1 are successfully expressed in P. pastoris and their products are directly secreted into the cultural supernatant at a high level of 1.0 g/L analyzed by thin-layer scanning. In addition, rVP1 alone could induce both humoral and marginal cell-mediated immune responses in mice, while the group with co-inoculations of rBoIFN-gamma could markedly enhance both humoral and cell-mediated immune responses; even more dramatic immune responses were observed with the group inoculated with the fusion product, rBoIFN-gamma/VP1. The fusion product could be further investigated for its utility of FMDV vaccine development.
Despite significant control efforts, foot-and-mouth disease (FMD) persists in Turkey, and new strains of serotypes A, O and Asia-1 are periodically reported to enter the country from the east. The status of FMD in Turkey is important regionally because the country forms a natural bridge between Asia where the disease is endemic, and Europe which has disease-free status. This study analysed spatial and temporal patterns of FMD occurrence in Turkey to explore factors associated with the disease's persistence and spread. Annual records of FMD distribution in Turkish provinces throughout 1990-2002, grouped by serotype (O, A and Asia 1), were analysed using geostatistical techniques to explore their spatial and temporal patterns. A meta-population model was used to test how disease status, expressed in terms of presence/absence, extinction, and colonization, and measured at the province level throughout the periods 1990-1996 and 1997 2002, could be predicted using province-level data on: ruminant livestock numbers; meat production-demand discrepancy (as a surrogate measure of animal and animal products marketing, i.e. long-distance contagion through the traffic of mainly live animals to urban centres); and the disease prevalence distribution as recorded for the previous year. A drastic overall reduction in FMD occurrence was observed from the period 1990-1996 to 1997-2002 when the disease was shown to retract into persistence islands. FMD occurrence was associated with host abundance, short distance contagion from adjacent provinces, and meat production-demand discrepancies. With FMD retracting into identified provinces, a shift in predictors of FMD occurrence was observed with a lower contribution of short-distance contagion, and a relatively higher association with meat production-demand discrepancies leading to live animal transport over long distances, and hence presenting opportunities for identifying critical-control points. The pattern of persistence differed according to serotype groups and is discussed in relation to their differential affinity to cattle and small ruminant hosts.
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BACKGROUND: Foot-and-mouth disease virus (FMDV) affects susceptible livestock animals and causes disastrous economic impact. Immunization with plasmid expressing VP1 that contains the major antigenic epitope(s) of FMDV as cytoplasmic protein (cVP1) failed to elicit full protection against FMDV challenge. MATERIALS AND METHODS: In this study, mice were immunized via electroporation with four cDNA expression vectors that were constructed to express VP1 of FMDV, as cytoplasmic (cVP1), secreted (sVP1), membrane-anchored (mVP1) or capsid precursor protein (P1), respectively, to evaluate whether expression of VP1 in specific subcellular compartment(s) would result in better immune responses. RESULTS: Electroporation enhanced immune responses to vectors expressing cVP1 or P1 and expedited the immune responses to vectors expressing sVP1 or mVP1. Immunization of mice via electroporation with mVP1 cDNA was better than sVP1 or cVP1 cDNA in eliciting neutralizing antibodies and viral clearance protection. Vaccination with P1 cDNA, nonetheless, yielded the best immune responses and protection among all four cDNAs that we tested. CONCLUSIONS: These results suggest that the antigenicity of a VP1 DNA vaccine can be significantly enhanced by altering the cellular localization of the VP1 antigen. Electroporation is a useful tool for enhancing the immune responses of vectors expressing VP1 or P1. By mimicking FMDV more closely than that of transgenic VP1 and eliciting immune responses favorably toward Th2, transgenic P1 may induce more neutralizing antibodies and better protection against FMDV challenge.
OBJECTIVE: To assess relative costs and benefits of vaccination and preemptive herd slaughter to control transmission of foot-and-mouth disease (FMD) virus (FMDV). SAMPLE POPULATION: 2,238 herds and 5 sale yards located in Fresno, Kings, and Tulare counties of California. PROCEDURE: Direct costs associated with indemnity, slaughter, cleaning and disinfecting livestock premises, and vaccination were compared for various eradication strategies. Additional cost, total program cost, net benefit, and benefit-cost value (B/C) for each supplemental strategy were estimated, based in part on results of published model simulations for FMD. Sensitivity analyses were conducted. RESULTS: Mean herd indemnity payments were estimated to be dollars 2.6 million and dollars 110,359 for dairy and nondairy herds, respectively. Cost to clean and disinfect livestock premises ranged from dollars 18,062 to dollars 60,205. Mean vaccination cost was dollars 2,960/herd. Total eradication cost ranged from dollars 61 million to dollars 551 million. All supplemental strategies involving use of vaccination were economically efficient (B/C range, 5.0 to 10.1) and feasible, whereas supplemental strategies involving use of slaughter programs were not economically efficient (B-C, 0.05 to 0.8) or feasible. CONCLUSIONS AND CLINICAL RELEVANCE: Vaccination with a highly efficacious vaccine may be a cost-effective strategy for control of FMD if vaccinated animals are not subsequently slaughtered and there is no future adverse economic impact, such as trade restrictions. Although less preferable than the baseline eradication program, selective slaughter of highest-risk herds was preferable to other preemptive slaughter strategies. However, indirect costs can be expected to contribute substantially more than direct costs to the total cost of eradication programs.
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