Advance on Foot-and-mouth Disease Virus

Foot-and-mouth disease (FMD) is an acute,febrile and highly contagious animal disease caused by foot-and-mouth disease virus (FMDV),and has been recognized as the most important constraint to international trade in animals and animal products.An outstanding feature for FMDV infection is that the FMDV infected animals may remain as a carrier state,some of the animals exposed to FMDV may have a long term asymptomatic infection.This article will review the advance of FMDV in the following aspects,epidemiology,etiology and pathogenesis.     

口蹄疫病毒研究进展

口蹄疫(foot-and-mouth disease,FMD)是由口蹄疫病毒(foot-and-mouth disease virus,FMDV)引起的一种急性、热性、高度接触传染性动物疫病,是全球范围内家畜及其产品贸易最大的羁绊。FMDV通过逃避宿主的免疫监视建立持续性感染,使患畜持续向外界排毒,成为传染源。作者查阅了近几年FMDV的国内外研究进展,对其流行病学、病原学及致病机理进行了概述。     

Detection of foot-and-mouth disease virus RNA in pharyngeal epithelium biopsy samples obtained from infected cattle: investigation of possible sites of virus replication and persistence

Foot-and-mouth disease (FMD) is a highly contagious viral infection of significant financial importance to the export and trade of agricultural products. The occurrence of persistently infected "carriers" of FMD-virus (FMDV) in ruminant species adds further complications to disease control. There have been significant discrepancies in reports regarding the pathogenesis of FMDV infection in cattle with specific emphasis on the anatomical sites involved in early and persistent virus replication. In this study, collection of small biopsy samples from the dorsal soft palate (DSP) of live animals was used to investigate the level of FMDV RNA present at this site at sequential time points during the infection. Results were compared to measurements of virus excretion in samples of oropharyngeal fluid collected at corresponding time points. Possible sites of virus persistence were investigated through measurements of the levels of FMDV RNA in the DSP as well as mandibular and retropharyngeal lymph nodes beyond 28 days after infection. Results indicated only low levels of FMDV RNA present in samples of pharyngeal epithelia during both early and persistent phases of infection with significantly higher levels of virus detected in pharyngeal excretions. It is concluded that the targeted area for sampling within the DSP does not harbour significant levels of virus replication during acute or persistent FMDV infection in cattle. Furthermore, the DSP and the mandibular and retropharyngeal lymph nodes cannot be concluded to be principal sites for persistence of FMDV.     

The relationship between cellular immune response to foot-and-mouth disease virus Asia 1 and viral persistence in Indian cattle (Bosindicus)

Foot-and-mouth disease (FMD), the most contagious animal disease, is associated with persistent viral infection in ruminants, despite the induction of systemic immune response. The present study was performed to decipher the relation between the persistent FMD virus (FMDV) infection and cellular immune response in Indian cattle (Bosindicus) following experimental inoculation of FMDV Asia 1. Persistent viral infection (carriers) was detected by antigen capture RT-PCR on the oesophageal-pharyngeal fluid. Viral excretion was found to be intermittent and strongly variable among the persistently infected Indian cattle. Lymphocyte proliferative (LP) response, assessed as reactivity of peripheral blood mononuclear cells to FMDV Asia 1 antigen (Ag) was of low magnitude indicating a weak primary cellular immune response following infection. LP response to FMDV Ag was higher among the non-carriers than carriers of FMDV Asia 1. An enhanced LP response was associated with the lack of virus shedding in the OPF. The findings of this study are suggestive of relationship between cellular immune response and virus excretion during persistence of FMDV Asia 1 in infected cattle.     

口蹄疫病毒免疫学研究进展

口蹄疫病毒(FMDV)是小RNA病毒科、口蹄疫病毒属成员,其感染后引起的口蹄疫是一种严重危害畜牧业发展的传染病,并对经济发展、国家声誉及国际关系造成重要影响.论文就FMDV的主要抗原位点、FMDV的细胞受体、机体对FMDV抗原的免疫反应、FMDV抗原的变异与进化等做一综述.     

Induction of lymphopenia and inhibition of T cell function during acute infection of swine with foot and mouth disease virus (FMDV)

Foot and mouth disease virus (FMDV) is a picornavirus that causes an acute vesicular disease of cloven-hoofed animals. This virus continues to be a threat to livestock worldwide with outbreaks causing severe economic losses. The present study shows an analysis of immune system phenotype and function during the acute phase of FMDV infection in swine. In the first days of infection, a significant lymphopenia is observed that involves all T cell subsets, CD4(+), CD8(+), and CD4(+)/CD8(+). This marked lymphopenia is not a result of active infection of PBMC with the virus. Further, the response of residual peripheral blood T cells to the mitogen, Concanavalin A (ConA) is significantly reduced and occasionally eliminated. Animals usually resolve clinical signs of disease and develop antigen specific T cell responses to the virus and recover ConA reactivity. These characteristics of acute phase infection likely play an important role in viral pathogenesis, propagation and shedding of viral particles and may be targeted as a way of improving vaccine formulations.     

Evaluation of a 3A-truncated foot-and-mouth disease virus in pigs for its potential as a marker vaccine

Foot-and-mouth disease (FMD) is a highly contagious and economically devastating disease of cloven-hoofed animals in the world. The disease can be effectively controlled by vaccination of susceptible animals with the conventional inactivated vaccine. However, one major concern of the inactivated FMD virus (FMDV) vaccine is that it does not allow serological discrimination between infected and vaccinated animals, and therefore interferes with serologic surveillance and the epidemiology of disease. A marker vaccine has proven to be of great value in disease eradication and control programs. In this study, we constructed a marker FMDV containing a deletion of residues 93 to 143 in the nonstructural protein 3A using a recently developed FMDV infectious cDNA clone. The marker virus, r-HN/3A_93–143, had similar growth kinetics as the wild type virus in culture cell and caused a symptomatic infection in pigs. Pigs immunized with chemically inactivated marker vaccine were fully protected from the wild type virus challenge, and the potency of this marker vaccine was 10 PD₅₀ (50% pig protective dose) per dose, indicating it could be an efficacious vaccine against FMDV. In addition, we developed a blocking ELISA targeted to the deleted epitope that could clearly differentiate animals infected with the marker virus from those infected with the wild type virus. These results indicate that a marker FMDV vaccine can be potentially developed by deleting an immunodominant epitope in NSP 3A.     

口蹄疫病毒感染细胞的研究进展

口蹄疫是引起偶蹄动物的急性发热性水泡性疾病,具有高度接触传染性,对发病国家和地区经济有破坏性作用和不良的政治影响。口蹄疫病原体为小RNA病毒科的口蹄疫病毒,是一类单股正链RNA病毒,该病毒有多种血清型及其亚型,相互之间无交叉保护力或保护力极其有限。目前,口蹄疫病毒感染的分子机理还不是很清楚。口蹄疫病毒感染细胞的过程主要包括病毒与细胞的吸附、病毒穿透细胞壁进入细胞、病毒粒子的脱衣壳、病毒RNA的翻译转录、病毒基因组的复制以及病毒粒子的成熟过程,最后是成熟的病毒粒子衣壳包装成为完整病毒。文章就口蹄疫病毒感染细胞的过程做一概述。     

Kinetics of immune response to foot-and-mouth disease virus (type Asia 1) in experimental cattle

Humoral and mucosal (secretory antibody)immune response to FMDV type Asia 1 in cattle was analyzed after vaccination and infection using virus neutralizing test (VNT). Vaccination (1/16th the usual dose) failed to protect cattle from generalized clinical disease following experimental FMDV Asia 1 infection. Our results showed that infection induced higher and prolonged serum antibody titres indicating antigen mass is important for optimal immune response. Experimental FMDV infection induced significant secretory antibody (mucosal) response in cattle. Though, there was no difference in the serum antibody response between the cattle that developed generalized infection (unprotected) and those with only localized infection (protected), secretory antibody response differed, wherein the unprotected cattle had higher secretory response than protected cattle. Thus, FMDV Asia 1 infection stimulates a similar serum antibody response and a unique secretory antibody response among the infected cattle. An erratum to this article can be found at     

口蹄疫病毒利用自身蛋白逃逸宿主天然免疫应答的研究进展

口蹄疫（foot-and-mouth disease,FMD）是由口蹄疫病毒（foot-and-mouth disease virus,FMDV）感染偶蹄兽所引起的一种急性、热性、高度接触性传染病,FMDV有7个血清型,加之病毒传播迅速,严重影响畜牧业的发展。FMDV为小RNA病毒科、口蹄疫病毒属的唯一成员,其基因组编码4种结构蛋白和10种非结构蛋白。FMDV感染宿主后利用自身蛋白通过多种途径和方式来影响宿主天然免疫应答,从而有利于FMDV复制的微环境。这些策略包括FMDV参与细胞自噬、内质网应激和应激颗粒形成的细胞过程,破坏多种宿主蛋白的功能,如劫持、裂解宿主蛋白或干扰宿主蛋白的表达、去除宿主蛋白的泛素化以及抑制宿主蛋白的磷酸化。这些逃避天然免疫的策略也是目前研究的热点。基于现有的研究结果,作者总结了近几年FMDV蛋白在抑制宿主天然免疫方面的研究进展,以期为FMDV的研究与防控提供参考。     

A replication analysis of foot-and-mouth disease virus in swine lymphoid tissue might indicate a putative carrier stage in pigs

ABSTRACT: Foot-and-mouth disease virus (FMVD), one of the most contagious viruses of cloven-hoofed animals, may cause a prolonged, asymptomatic but persistent infection in ruminants, named the "carrier state". However, it remains an open question whether this carrier state occurs in pigs. Here we present quantitative analyses of the duration of FMDV RNA and infectivity in lymphoid and epithelial tissues in experimentally infected pigs with FMDV C-S8c1. The data indicated that although FMDV RNA remained in blood until day 14 post-infection (pi), viremia was cleared by day 7 pi. However, all tissues tested were positive for FMDV until day 14-17 pi. Interestingly, the specific infectivity of FMDV in these tissues was in some cases even higher than the FMDV C-S8c1. We therefore propose that a "pseudopersistent state" may occur in pigs in which virus replicates in lymphoid tissues for a prolonged period of time, thereby representing a potential source of virus.     

Recent Advance on Foot-and-Mouth Disease Virus Utilizes Self-proteins to Evade Innate Immunity Response of Host

Foot-and-mouth disease (FMD) is an acute, hot, and highly contagious infectious disease caused by foot-and-mouth disease virus (FMDV) infection of cloven-hoofed animals. FMDV has seven serotypes and it spreads rapidly, which seriously affects the development of animal husbandry. FMDV is the prototype member of the Aphthovirus genus within the Picornaviridae family, and its genome encodes 4 structural proteins and 10 non-structural proteins. After infecting the host, FMDV uses its proteins to affect the host innate immune response through a variety of pathways and methods, which is beneficial to the microenvironment of FMDV replication. These strategies include FMDV involvement in autophagy, endoplasmic reticulum stress and stress granule formation of cellular processes, subverting the functions of various host proteins, such as hijacking, cleaving host proteins or interfering with the expression of host proteins, removing ubiquitin from host proteins, and inhibiting the phosphorylation of host proteins, which are also the focus of current research. Based on the existing research results, we summarized the research progress of FMDV protein in suppressing the innate immunity of host in recent years, intending to provide a reference for the research and prevention of FMDV.     

口蹄疫病毒抗原胶体金试纸条的研究

利用单克隆抗体技术制备抗口蹄疫病毒的单克隆抗体,特异性试验表明其只与O、A、Asia 1型3种血清型FMDV抗原结合。进而采用胶体金标记技术,以胶体金标记的抗口蹄疫病毒单克隆抗体、多克隆血清抗体和葡萄球菌A蛋白为主要材料,研制口蹄疫快速检测试纸条。该试纸条检测O、A、Asia 1型3种血清型灭活口蹄疫病毒均为阳性,检测水疱性口炎病毒、猪水疱病病毒、蓝舌病病毒、猪蓝耳病病毒4种灭活抗原及小反刍兽疫病毒疫苗株均为阴性,试验结果与口蹄疫实时荧光定量RT-PCR方法的完全一致,表明其具有良好的特异性。敏感性试验结果是,试纸条的检测极限为1∶160稀释的样品,其敏感性相当于实时荧光定量RT-PCR方法的1/64。由于试纸条具有操作方便、检测快速等优点,因此该试纸条可以用于大量临床样品的快速检测和现场检测。     

Proteomics analysis of porcine serum proteins by LC-MS/MS after foot-and-mouth disease virus (FMDV) infection

To analyze serum proteomics differences between normal and foot and mouth disease virus (FMDV)-infected piglets, an analytical method based on liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used. Samples of venous blood were collected before and after FMDV infection and high abundance serum albumin was removed using a commercial kit. After trypsin digestion, serum samples were processed with LC-MS/MS. Proteins were identified by peptide mass fingerprinting. We found that apolipoprotein A-IV precursor, haptoglobin and probable chemoreceptor glutamine deamidase cheD appeared after FMDV infection in the same piglet. This is believed to be the first time that serum proteomics analysis by LC-MS/MS after FMDV infection has been performed, and our results may provide further information about biomarkers for early diagnosis of FMD in piglets.     

Carriers of foot-and-mouth disease virus: a review

This review describes current knowledge about persistent foot-and-mouth disease virus (FMDV) infections, the available methods to detect carrier animals, the properties of persisting virus, the immunological mechanisms, and the risk of transmission. In particular, knowledge about the carrier state, the period in which virus can be isolated from animals 28 days or longer post infection, is important, because the risk that animals may carry the virus will influence the diagnostic and preventive measures that need to be taken. Although many years of research have led to much knowledge about foot-and mouth disease and its causative agent, there are still numerous aspects of the virus and the disease that are not yet fully understood. Areas for further research on persistence of FMDV are discussed.     

Current status of foot-and-mouth disease vaccines including the use of genetic engineering

SUMMARY Foot-and-mouth disease virus (FMDV) vaccines are used to protect animals against infection by the 7 FMDV serotypes composed of greater than 60 FMDV subtypes. Because of problems of both live attenuated and inactivated FMDV vaccines and also because of the very large market for an effective safe vaccine, research into other types of vaccines has been undertaken. One of the 4 virus structural proteins, VP1, is believed to be the main protein that stimulates virus neutralising antibodies and studies have concentrated on its potential as a subunit vaccine. Genetic engineering has been used to clone the VF1 gene of FMDV and VP1 synthesised from the cloned gene has been used in experimental vaccine studies. The studies in small numbers of cattle and pigs demonstrated that 2 vaccinations with genetically engineered VP1 could confer protection against FMDV challenge. However, there are a number of areas that need further research before such a genetically engineered vaccine could be used commercially. The use of chemically synthesised antigenic fragments of VP1 has recently been reported, and these synthetic fragments appear to be potentially better at producing immunity to FMDV than the whole genetically engineered VP1 protein, perhaps because of conformational problems in the presentation of whole VP1. Other possible future directions in the research and in the development of safe, effective FMDV vaccines are discussed. In conclusion, although very significant progress has been made in cloning FMDV-VP1 genes, we are still far from a genetically engineered VP1-FMDV subunit vaccine. In the meantime, properly inactivated and safety-tested FMDV vaccines will continue to be used and to be of benefit to the livestock industry in countries where foot-and-mouth is endemic or in combating introductions of the disease.     

Foot-and-mouth disease virus in the llama (Lama glama): diagnosis, transmission, and susceptibility

Foot-and-mouth disease virus (FMDV) was shown to be transmitted from either cattle to llamas, llamas to swine (interspecies), or llamas to llamas (intraspecies). Response to FMDV varied greatly in the 6 llamas studied; 3 llamas developed generalized clinical disease with mild pyrexia, 2 after intradermolingual inoculation, and 1 after exposure to a calf infected with FMDV serotype A24. Another contact llama developed vesicular lesions on all 4 extremities but no oral lesions. Two contact llamas, in separate study groups, did not seroconvert or develop clinical signs of FMDV infection. All 4 llamas showing clinical disease developed virus-neutralizing antibodies against FMDV A24 and antibodies against the virus-infection-associated antigen. Virus-neutralizing antibody titers remained elevated for over 200 days postinoculation or exposure. Antibodies to virus-infection-associated antigen were detected several days after virus-neutralizing antibody appeared and became weaker 100-125 days post-FMDV exposure in 3 of the 4 clinically affected llamas. One inoculated llama was still positive for virus-infection-associated antigen at 360 days after inoculation. Foot-and-mouth disease virus A24 was not detected from esophageal-pharyngeal fluid specimens beyond 8 days postexposure using in vitro techniques.