Global Foot-and-Mouth Disease Research Alliance

Publications

ARS Plum Island

Other Contributors

Abstracts

Goal 1
Facilitate research collaborations and serve as a communication gateway for the global FMD research community [read more...]

Goal 2
Conduct strategic research to better understand Foot and Mouth Disease [read more...]

Objective 1. Understand host-pathogen interactions

Golde, W.T., Nfon, C.K., Toka, F.N.
Immune evasion during foot-and-mouth disease virus (FMDV) infection of swine.
(2008) Immunological Reviews, 225, pp. 85-95.
Plum Island Animal Disease Center, ARS, USDA, Greenport, NY 11944-0848, USA.
Corresponding author: william.golde@ars.usda.gov
View Abstract

Abstract: The interface between successful pathogens and their hosts is often a tenuous balance. In acute viral infections, this balance involves induction and inhibition of innate responses. Foot-and-mouth disease virus (FMDV) is considered one of the most contagious viruses known and is characterized by rapid induction of clinical disease in cloven hoofed animals exposed to infection. Viral shedding is extensive before the equally rapid resolution of acute disease. This positive strand RNA virus is an extremely successful pathogen, due in part to the ability to interrupt the innate immune response. Previous reviews have described the inhibition of cellular innate responses in the infected cell both in vitro and in vivo. Here, we present a review of virus inhibition of cells that are a source of antiviral function in swine. Particularly in the case of dendritic cells and natural killer cells, the virus has evolved mechanisms to interrupt the normal function of these important mediators of innate function, even though these cells are not infected by the virus. Understanding how this virus subverts the innate response will provide valuable information for the development of rapidly acting biotherapeutics to use in response to an outbreak of FMDV.

Grubman, M.J., Moraes, M.P., Diaz-San Segundo, F., Pena, L., De Los Santos, T.
Evading the host immune response: How foot-and-mouth disease virus has become an effective pathogen.
(2008) FEMS Immunology and Medical Microbiology, 53 (1), pp. 8-17.
Plum Island Animal Disease Center, Agricultural Research Service, US Department of Agriculture, Greenport, New York 11944, USA.
Corresponding author: marvin.grubman@ars.usda.gov
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Abstract: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. In this review, we discuss the mechanisms FMDV has evolved to counteract the host innate and adaptive immune responses and the role of viral proteins in this process. The viral leader proteinase, L pro, limits the host innate response by inhibiting the induction of interferon beta (IFN beta) mRNA and blocking host cell translation. A second viral proteinase, 3C pro, may affect host cell transcription because it cleaves histone H3. Viral protein 2B in conjunction with 2C or their precursor 2BC inhibits protein trafficking through the endoplasmic reticulum and Golgi apparatus. A decrease in surface expression of major histocompatibility class I molecules during FMDV infection suggests that 2B, 2C and/or 2BC may be involved in delaying the initiation of the host adaptive immune response and also adversely affect the secretion of induced signaling molecules. FMDV also ca uses a transient lymphopenia in swine, but the mechanism involved is not understood nor have any viral protein(s) been implicated. Furthermore, the interaction of FMDV with various cells in the immune system including lymphocytes and dendritic cells and the possible role of apoptosis and autophagy in these interactions are discussed.

Nfon, C.K., Ferman, G.S., Toka, F.N., Gregg, D.A., Golde, W.T.
Interferon-a production by swine dendritic cells is inhibited during acute infection with foot-and-mouth disease virus.
(2008) Viral Immunology, 21 (1), pp. 68-77.
Plum Island Animal Disease Center, ARS, USDA, Greenport, NY 11944-0848, USA.
Corresponding author william.golde@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFNs). We have previously reported that exposure of dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong type I IFN (IFN-alpha and IFN-beta) response, indicating that DCs may play a critical role in the innate response to the virus. In vivo, FMDV induces lymphopenia and reduced T-cell proliferative responses to mitogen, viral effects that may contribute to evasion of early immune responses. In this study we analyzed the in vivo effects of FMDV infection on the IFN-alpha response of two populations of dendritic cells. During the acute phase of infection of swine, production of IFN-alpha from monocyte-derived DCs (MoDCs) and skin-derived DCs (skin DCs) is inhibited. This effect occurs concurrently with rising viral titers in the blood; however, these cells are not productively infected. Interestingly, there are no changes in the capability of these DCs to take up particles and process antigens, indicating that antigen-presenting cell function is normal. These data indicate that inhibition of the IFN-alpha response of dendritic cell populations from blood and skin by FMDV enhances viral pathogenesis in infected animals.

O'Donnell, V.O., LaRocco, M., Baxt, B.
Heparan sulfate-binding Foot-and-Mouth Disease Virus enters cells via caveolae-mediated endocytosis.
(2008) Journal of Virology, 82 (18), pp. 9075-9085.
USDA, ARS, Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944-0848, USA.
Corresponding author: vivian.odonnell@ars.usda.gov
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Document Type: Article
Abstract: Foot-and-mouth disease virus (FMDV) utilizes different cell surface macromolecules to facilitate infection of cultured cells. Virus which is virulent for susceptible animals infects cells via four members of the V subclass of cellular integrins. In contrast, tissue culture adaptation of some FMDV serotypes results in the loss of viral virulence in the animal accompanied by the loss of ability to use integrins as receptors. These avirulent viral variants acquire positively charged amino acids on surface-exposed structural proteins resulting in the utilization of cell surface heparan sulfate (HS) molecules as receptors. We have recently shown that FMDV serotypes utilizing integrin receptors enter cells via a clathrin-mediated mechanism into early endosomes. Acidification within the endosome results in a breakdown of the viral capsid releasing the RNA, which enters the cytoplasm by a still undefined mechanism. Since there is evidence that HS internalizes bound ligands via a caveolae-mediated mechanism, it was of interest to analyze the entry of FMDV by cell-surface HS. Using a genetically engineered variant of type O1Campos (O1C3056R) which can utilize both integrins and HS as receptors, and a second variant (O1C3056R-KGE), which can only utilize HS as a receptor, we followed viral entry using confocal microscopy. After binding virus to cells at 4°C, followed by shifting the temperature to 37°C, type O1C3056R-KGE colocalized with caveolin-1 while O1C3056R colocalized with both clathrin and caveolin-1. Compounds which either disrupt or inhibit the formation of lipid rafts inhibit the replication of O1C3056R-KGE. Furthermore, a caveolin-1 knockdown by RNA interference also considerably reduced the efficiency of O1C3056R-KGE infection. These results indicate that HS-binding FMDV, enters the cells via the caveolae-mediated endocytosis pathway and caveolae can associate and traffic with endosomes. In addition, these results further suggest that the route of FMD V entry into cells is a function solely of the viral receptor.

Oem, J.K., Yeh, M.T., McKenna, T.S., Hayes, J.R., Rieder, E., Giuffre, A.C., Robida, J.M., Lee, K.N., Cho, I.S., Fang, X., Joo, Y.S., Park, J.H.
Pathogenic Characteristics of the Korean 2002 Isolate of Foot-and-Mouth Disease Virus Serotype O in pigs and cattle. (2008) Journal of Comparative Pathology, 138 (4), pp. 204-214.
National Veterinary Research and Quarantine Service, Foreign Animal Disease Research Division, Ministry of Agriculture, 480 Anyang-6-Dong, Anyang 430-824, Republic of Korea
Corresponding author: parkjh@nvrqs.go.kr
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DOCUMENT TYPE: Article
Abstract: Experimental infection of susceptible cattle and pigs showed that the O/SKR/AS/2002 pig strain of foot-and-mouth disease virus (FMDV) causes an infection that is highly virulent and contagious in pigs but very limited in cattle. Pigs directly inoculated with, or exposed to swine infected with, strain O/SKR/AS/2002 showed typical clinical signs, including gross vesicular lesions in mouth and pedal sites. In addition, FMDV was isolated from, and FMDV genomic RNA was detected in, blood, serum, nasal swabs and oesophageal-pharyngeal (OP) fluid early in the course of infection. Antibodies against the non-structural protein (NSP) 3ABC were detected in both directly inoculated and contact pigs, indicating active virus replication. In contrast, the disease in cattle was atypical. After inoculation, lesions were confined to the infection site. A transient viraemia occurred 1 and 2 days after inoculation, and this was followed by the production of antibodies to NSP 3ABC, indicating subclinical infection. No clinical disease was seen, and no antibodies to NSP 3ABC were present in contact cattle. Additionally, no virus or viral nucleic acid was detected in blood, nasal swab and OP fluid samples from contact cattle. Thus, the virus appeared not to be transmitted from infected cattle to contact cattle. In its behaviour in pigs and cattle, strain O/SKR/AS/2002 resembled the porcinophilic FMDV strain of Cathay origin, O/TAW/97. However, the latter, unlike O/SKR/AS/2002, has reduced ability to grow in bovine-derived cells. The porcinophilic character of O/TAW/97 has been attributed to a deletion in the 3A coding region of the viral genome. However, O/SKR/AS/2002 has an intact 3A coding region.

Pacheco JM, Arzt J, Rodriguez LL.
Early events in the pathogenesis of foot-and-mouth disease in cattle after controlled aerosol exposure.
(2008) The Veterinary Journal, article in press.
Plum Island Animal Disease Center, Foot-and-Mouth Disease Unit PIADC, ARS, USDA, P.O. Box 848, Greenport, NY 11944, USA
Corresponding author: luis.rodriguez@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: The goal of this study was to identify the primary sites of replication of foot-and-mouth disease virus (FMDV) in cattle subsequent to aerogenous inoculation. A novel aerosol inoculation method was developed to simulate natural, airborne transmission and thereby allow the identification of early replication sites. Virus distribution after aerosol inoculation was compared at 24h post inoculation with simple nasal instillation. Aerosol inoculation of FMDV consistently resulted in virus detection by real-time reverse transcriptase-polymerase chain reaction and viral isolation in the soft palate, pharynx, and lungs. Viral antigen was also detected in each of these tissues by immunohistochemistry. Aerosol exposure resulted in typical clinical signs of FMD when animals were kept alive long enough to develop disease. This aerosol infection method is highly reproducible regarding inoculum dose and volume, and allowed the detailed study of early events in FMDV-infected cattle. Extensive postmortem sampling and trimodal virus detection system allows a more precise determination of FMDV localization than previously reported.

Mason P.W., Grubman M.J.
Foot-and-Mouth Disease. Chapter 22 from the book titled "Vaccines for Biodefense and Emerging and Neglected Diseases", by Alan D.T. Barrett and Lawrence R. Stanberry. Academic Press, c2009. ISBN: 9780123694089. pp. 361-377.
DOCUMENT TYPE: Book chapter
Corresponding author: marvin.grubman@ars.usda.gov
View Abstract

Book Chapter. No Abstract Available.

O'Donnell V., Pacheco J.M., Gregg D., Baxt B.
Analysis of Foot-and-Mouth Disease Virus integrin receptor expression in tissues from naïve and infected cattle.
(2009) Journal of Comparative Pathology (June 8, 2009).
United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, NY
Corresponding author: vivian.odonnell@ars.usda.gov
View Abstract

DOCUMENT TYPE: Article
Abstract: Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals principally affecting cattle, pigs and sheep. FMD virus (FMDV) uses the alpha(V)beta(1), alpha(V)beta(3), alpha(V)beta(6), and alpha(V)beta(8) integrins as receptors in vitro via a highly conserved arginine-glycine-aspartic acid amino acid sequence motif located within the betaG-betaH loop of VP1. Immunofluorescence and confocal microscopy were used to study the expression of two major FMDV receptors, alpha(V)beta(3) and alpha(V)beta(6), within epithelial tissues from FMDV-infected and uninfected cattle in order to understand the role of these receptors in tissue tropism. Integrin alpha(V)beta(6) was expressed by epithelial cells in tissues that are important sites for FMDV replication (i.e. tongue and coronary band). Integrin alpha(V)beta(3) was detected in epithelium of all tissues examined except tongue. In addition, alpha(V)beta(3) expression was associated with blood vessels in all tissues examined. In infected tissues, alpha(V)beta(6) integrin was distributed on the surface of those epithelial cells also expressing FMDV antigen. Although integrin alpha(V)beta(3) has been shown to be a receptor for FMDV, no expression of alpha(V)beta(3) was associated with FMDV-positive keratinocytes in the tongue. In contrast, podal epithelial cells containing FMDV antigen also expressed alpha(V)beta(3) integrin. Thus, at the cellular level the expression of these two integrins correlates with susceptibility to infection and may contribute substantially to viral tropism in FMD pathogenesis.

Piccone M.E., Feng Y., Chang A.C.Y., Mosseri R., Lu Q., Kutish G.F., Lu Z., Burrage T.G., Gooch C., Rock D.L., Cohen S.N.
Identification of cellular genes affecting the infectivity of Foot-and-Mouth Disease Virus.
(2009) Journal of Virology
Stanford University School of Medicine, Department of Genetics, 300 Pasteur Drive, Stanford, CA 94305-5120.
Corresponding author: sncohen@stanford.edu
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DOCUMENT TYPE: Article
Abstract: Foot-and-mouth disease virus (FMDV) produces one of the most infectious of all livestock diseases, causing extensive economic loss in areas of breakout. Like other viral pathogens, FMDV recruits proteins encoded by host cell genes to accomplish the entry, replication, and release of infectious viral particles. To identify such host-encoded proteins, we employed an antisense RNA strategy and a lentivirus-based library containing approximately 40,000 human expressed sequence tags (ESTs) to randomly inactivate chromosomal genes in a bovine kidney cell line (LF-BK) that is highly susceptible to FMDV infection and then isolated clones that survived multiple rounds of exposure to the virus. Here, we report the identification of ESTs whose expression in antisense orientation limited host cell killing by FMDV and restricted viral propagation. The role of one such EST, that of ectonucleoside triphosphate diphosphohydrolase 6 (NTPDase6; also known as CD39L2), a membrane-associated ectonucleoside triphosphate diphosphohydrolase that previously was not suspected of involvement in the propagation of viral pathogens and which we now show is required for normal synthesis of FMDV RNA and proteins, is described in this report.

Piccone M.E., Pauszek S., Pacheco J., Rieder E., Kramer E., Rodriguez L.L.
Molecular characterization of a foot-and-mouth disease virus containing a 57-nucleotide insertion in the 3'untranslated region.
(2009) Archives of Virology, 154 (4), pp.671-676.
Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, USDA/ARS/NAA, Greenport, NY, 11944-0848, USA.
Corresponding author: maria.piccone@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: A foot-and-mouth disease virus containing a 57-nucleotide (nt) insertion in the 3'untranslated region (3'UTR) was generated by transposon (tn)-mediated mutagenesis. Characterization of the mutant virus (A24-3'UTR8110) revealed no significant differences in virus growth, translation efficiency or virulence in cattle compared to the A24 wild-type virus. RNA modeling showed that the structures predicted in the 3'UTR were not affected by the tn insertion. These results revealed that the 3'UTR can tolerate foreign sequences that do not disrupt essential signals required for virus replication.

Rainwater-Lovett, K., Pacheco, J.M., Packer, C., Rodriguez, L.L.
Detection of foot-and-mouth disease virus infected cattle using infrared thermography.
(2009) The Veterinary Journal, June 2009, 180, (3), pp.317-324.
Plum Island Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, P.O. Box 848, Greenport, NY 11944, USA
Corresponding author: luis.rodriguez@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: In this study, infrared thermography (IRT) was assessed as a means of detecting foot-and-mouth disease virus (FMDV)-infected cattle before and after the development of clinical signs. Preliminary IRT imaging demonstrated that foot temperatures increased in FMDV-infected animals. The maximum foot temperatures of healthy (n=53), directly inoculated (DI) (n=12), contact (CT) (n=6), and vaccine trial (VT) (n=21) cattle were measured over the course of FMD infection. A cut-off value was established at 34.4 degrees C (sensitivity=61.1%, specificity=87.7%) with the aim of detecting FMDV-infected animals both before and after clinical signs were observed. Seven of 12 (58%) DI and 3/6 (50%) CT animals showed maximum foot temperatures exceeding the 34.4 degrees C cut-off before the development of foot vesicles. In contrast, only 5/21 (24%) VT animals displayed pre-clinical foot temperatures above this cut-off possibly indicating partial vaccine protection of this group. These results show IRT as a promising screening technology to quickly identify potentially infected animals for confirmatory diagnostic testing during FMD outbreaks. Further evaluation of this technology is needed to determine the value of IRT in detecting animals with mild clinical signs or sub-clinical infections.

Toka F.N., Nfon C.K., Dawson H., Estes D.M., Golde W.T.
Activation of porcine natural killer cells and lysis of Foot-and-Mouth Disease Virus infected cells.
(2009) Journal of Interferon & Cytokine Research, 29 (3), pp. 47-60.
Plum Island Animal Disease Center, U.S. Department of Agriculture, Greenport, New York 11944, USA.
Corresponding author: william.golde@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: Natural killer (NK) cells play a vital role in innate response against viral infections and cellular transformation. In vivo modulation of their response may enhance their antiviral function. Here we describe the phenotype of porcine NK cells, test potential proinflammatory cytokines for activation of these cells and assess the capability of porcine NK cells to kill virus-infected or tumor cells in vitro. The CD2(+)/CD8(+)/CD3(-) cell compartment contained porcine NK cells, which at the resting stage were minimally cytotoxic toward foot-and-mouth disease virus (FMDV)-infected porcine cells or tumor cell lines. Direct stimulation of NK cells with proinflammatory cytokines induced efficient lysis of FMDV-infected cells with interleukin (IL)-2 or IL-15 showing the highest stimulatory capacity. Lower levels of NK cell activation were induced by IL-12, IL-18, or interferon (IFN)-alpha, however, IL-12 and IL-18 synergistically activated NK cells. Combinations of IL-15 and IL-12 or IL-15 and IL-18 did not further increase the porcine NK cell lytic capability over IL-15 alone. Natural killer cells expressed IFN-gamma regardless of the cytokine used for stimulation while expression of perforin increased modestly. The enhancement of porcine NK cell activity by proinflammatory cytokines offers a promising tool for development of antiviral approaches against virus infection.

Toka F.N., Nfon C.K., Dawson H., Golde W.T.
Accessory cell mediated activation of porcine NK cells by TLR7 and TLR8 agonists.
(2009) Clinical and Vaccine Immunology
Plum Island Animal Disease Center, U.S. Department of Agriculture, Greenport, New York 11944, USA.
Corresponding author: william.golde@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: The induction of innate immune responses by toll-like receptor (TLR) agonists is the subject of intense investigation. In large part, this reflects the potential of such compounds to be effective vaccine adjuvants. For that reason, we analyzed the activation of innate cells in swine by TLR7 and TLR8 agonists. These agonists activated porcine NK cells by increasing gamma interferon (IFN-gamma) expression and perforin storage. The activation of porcine NK cells was mediated by accessory cells, since their depletion resulted in reduced cytotoxicity toward target cells. Accessory cells were stimulated to produce interleukin 12 (IL-12), IL-15, IL-18, and IFN-alpha after treatment with TLR7 or TLR8 agonists. Neutralization of these cytokines reduced but did not completely inhibit the induction of NK cell cytotoxicity. Direct stimulation of NK cells with TLR7 or TLR8 agonists resulted in minimal cytotoxicity but levels of IFN-gamma equivalent to those detected in the presence of accessory cells. Porcine NK cells express both TLR7 and TLR8 mRNAs, and treatment with these TLR agonists induced higher mRNA expression levels of TLRs and IL-15Ralpha, which may contribute to the activity of NK cells. These data indicate that TLR7 and TLR8 agonists indirectly or directly activate porcine NK cells but that optimum levels of activation require cytokine secretion by accessory cells activated by these compounds. Interestingly, NK cells activated by TLR7 or TLR8 agonists were cytotoxic against foot-and-mouth disease virus (FMDV)-infected cells in vitro, indicating that these TLR agonists may be beneficial as adjuvants to stimulate the innate immunity against FMDV.

Objective 2.3 Understand the epidemiology of FMD

Schumann, K.R., Knowles, N.J., Davies, P.R., Midgley, R.J., Valarcher, J-F., Raoufi, A.Q., McKenna, T.S., Hurtle, W., Burans, J.P., Martin, B.M., Rodriguez, L.L., Beckham, T.R.
Genetic characterization and molecular epidemiology of foot-and-mouth disease viruses isolated from Afghanistan in 2003-2005. (2008) Virus Genes, April 2008, 36 (2), pp. 401-413.
Foreign Animal Disease Diagnostic Laboratory, National Veterinary Services Laboratories, Veterinary Services, Animal and Plant Health Inspection Service, United States Department of Agriculture, Orient Point, NY 11957, USA.
Corresponding author: Kate.R.Schumann@aphis.usda.gov
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DOCUMENT TYPE: Article
Abstract: Foot-and-mouth disease virus (FMDV) isolates collected from various geographic locations in Afghanistan between 2003 and 2005 were genetically characterized, and their phylogeny was reconstructed utilizing nucleotide sequences of the complete VP1 coding region. Three serotypes of FMDV (types A, O, and Asia 1) were identified as causing clinical disease in Afghanistan during this period. Phylogenetic analysis revealed that the type A viruses were most closely related to isolates collected in Iran during 2002-2004. This is the first published report of serotype A in Afghanistan since 1975, therefore indicating the need for inclusion of serotype A in vaccine formulations that will be used to control disease outbreaks in this country. Serotype O virus isolates were closely related to PanAsia strains, including those that originated from Bhutan and Nepal during 2003-2004. The Asia 1 viruses, collected along the northern and eastern borders of Afghanistan, were most closely related to FMDV isolates collected in Pakistan during 2003 and 2004. Data obtained from this study provide valuable information on the FMDV serotypes circulating in Afghanistan and their genetic relationship with strains causing FMD in neighboring countries.

De los Santos, T., Diaz-San Segundo F., Zhu J., Koster M., Dias C.C.A., Grubman M.J.
A conserved domain in the leader proteinase of Foot-and-Mouth Disease Virus is required for proper subcellular localization and function.
(2009) Journal of Virology, 83 (4), pp. 1800-1810.
Plum Island Animal Disease Center, U.S. Department of Agriculture, Greenport, New York 11944, USA.
Corresponding author: teresa.delossantos@ars.usda.gov
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DOCUMENT TYPE: Article
Abstract: The leader proteinase (L(pro)) of foot-and-mouth disease virus (FMDV) is involved in antagonizing the innate immune response by blocking the expression of interferon (IFN) and by reducing the immediate-early induction of IFN-beta mRNA and IFN-stimulated genes. In addition to its role in shutting off cap-dependent host mRNA translation, L(pro) is associated with the degradation of the p65/RelA subunit of nuclear factor kappaB (NF-kappaB). Bioinformatics analysis suggests that L(pro) contains a SAP (for SAF-A/B, Acinus, and PIAS) domain, a protein structure associated in some cases with the nuclear retention of molecules involved in transcriptional control. We have introduced a single or a double mutation in conserved amino acid residues contained within this domain of L(pro). Although three stable mutant viruses were obtained, only the double mutant displayed an attenuated phenotype in cell culture. Indirect immunofluorescence analysis showed that L(pro) subcellular distribution is altered in cells infected with the double mutant virus. Interestingly, nuclear p65/RelA staining disappeared from wild-type (WT) FMDV-infected cells but not from double mutant virus-infected cells. Consistent with these results, NF-kappaB-dependent transcription was not inhibited in cells infected with double mutant virus in contrast to cells infected with WT virus. However, degradation of the translation initiation factor eIF-4G was very similar for both the WT and the double mutant viruses. Since L(pro) catalytic activity was demonstrated to be a requirement for p65/RelA degradation, our results indicate that mutation of the SAP domain reveals a novel separation-of-function activity for FMDV L(pro).

Perez, A.M., Zeng, D., Tseng, C.J., Chen, H., Whedbee, Z., Paton, D., Thurmond, M.C.,
A Web-based system for near real-time surveillance and time-space cluster analysis of animal diseases.
(2009) Preventive Veterinary Medicine. In press: 10.1016/j.prevetmed.2009.05.006
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

Considerable attention has been given lately to the need for global systems for animal disease surveillance that support real-time assessment of changing temporal-spatial risks. Until recently, however, prospects for development of such systems have been limited by the lack of informatics tools and an overarching collaboration framework to enable real-time data capturing, sharing, analysis, and related decision-making. In this paper, we present some of the tools of the FMD BioPortal System (www.fmd.ucdavis.edu/bioportal), which is a web-based system that facilitates near real-time information sharing, visualization, and advanced space-time cluster analysis for foot-and-mouth disease (FMD). Using this system, FMD information that is collected and maintained at various data acquisition and management sites around the world can be submitted to a data repository using various mutually agreed upon Extensible Markup Language (XML) formats, including Health Level Seven (HL7). FMD BioPortal makes available a set of advanced space-time cluster analysis techniques, including scan statistic-based methods and machine learning-based clustering methods. These techniques are aimed at identifying local clusters of disease cases in relation to the background risk. Data and analysis results can be displayed using a novel visualization environment, which supports multiple views including GIS, timeline, and periodical patterns. All FMD BioPortal functionalities are accessible through the Web and data confidentiality can be secured through user access control and computer network security techniques such as Secure Sockets Layer (SSL). FMD BioPortal is currently operational with limited data routinely collected by the Office International des Epizooties, the GenBank, the FMD World Reference Laboratory in Pirbright, and by the FMD Laboratory at the University of California in Davis. Here we describe technical attributes and capabilities of FMD BioPortal and illustrate its functionality by analyzing and displaying information from a simulated FMD epidemic in California.

Perez, A.M., Thurmond, M.C., Carpenter, T.E., Grant, P.W.
Use of the scan statistic on disaggregated province-based data: Foot-and Mouth Disease in Iran.
(2005) Preventive Veterinary Medicine, 71, pp. 197-207.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
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The spatial scan statistic was applied to density-smoothed data that approximated the spatial distribution within the area and reduced the potential bias produced when location data have been aggregated for large areas. The method is illustrated, using data on the location of foot-and-mouth disease (FMD) outbreaks in Iran. Data examined were 4477 FMD outbreaks reported on a per province basis between June 1996 and September 2003. A kernel density of the outbreak locations was estimated, using a fixed radius and the centroid of each province as the designated location of all cases reported for the province. The radius that produced a density map with the highest correlation with expert opinion was 4 degrees (latitude/longitude). Livestock density was used as a proxy for the underlying population at risk of acquiring FMD. Livestock and outbreak density maps were overlain to obtain the number of outbreaks and livestock in each of 15,599 cells covering the mapped surface of the country. A spatial scan statistic was applied to the density-smoothed data assuming that the outbreaks had a Poisson distribution. Results were compared with those obtained using a spatial scan statistic on provincially aggregated data. Application of the spatial scan statistic on the density-smoothed data allowed identification of clusters (P<0.01) related more to the actual geographic distribution of cases (expert opinion) and of animals at risk, than to the distribution of the provinces. Significant clusters of FMD were identified that coincided with roads, neighboring countries, and high-density population areas, suggesting that the region may represent a route for cross-continent transmission of FMD.

Perez, A.M., Thurmond, M.C., Carpenter, T.E.
Spatial distribution of foot-and-mouth disease in Pakistan estimated using imperfect data.
(2006) Preventive Veterinary Medicine, 76, pp. 280-289.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

We estimated the spatial distribution of foot-and-mouth disease (FMD) in Pakistan; we used a probability co-kriging model and the number of FMD outbreaks reported between 1996 and 2000 by Pakistan to the Office International des Epizooties. We used a k-Bessel model and small-ruminant and human densities as surrogate covariates for the population at risk and for livestock markets and movements, respectively. Compared to no or only one covariate, the co-kriging model with both densities provided the best fit to independently obtained data on the spatial distribution of virus isolations (P=0.57). The estimated probability of an FMD outbreak per 25km(2) cell ranged from 0.017 to 0.812, with the maximum relative probability of 47.8 (0.812/0.017). Areas with the highest relative probability of having an FMD outbreak were located in the Punjab region; this is a major animal-production area located along a traditional international animal-trade route.

Gallego, M., Perez, A.M., Thurmond, M.C.
Temporal and spatial distributions of foot-and-mouth disease under three different strategies of control and eradication in Colombia (1982-2003).
(2006) Veterinary Research Communications, 31, pp. 819-834.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

Outbreaks of foot-and-mouth disease (FMD) from January 1982 through December 2003 were used to examine variations in serotype- and species-specific risk for three control programmes in Colombia: (1982-1983) vaccination, using an aluminium hydroxide, saponin adjuvant, required but not enforced; (1984-1996) vaccination, using an oil double-emulsion adjuvant, required but not enforced; and (1997-2003) enforced vaccination, using an oil double-emulsion adjuvant, restricted animal movement enforced, and slaughter of infected animals. Hypotheses were tested for trend, cyclicity and seasonality in FMD occurrence, and for species- and serotype-specific differences in morbidity and case-fatality. The spatial density of outbreaks was estimated by kernel smoothing. The frequency of outbreaks decreased most between 1984 and 1996 (p < 0.01) for serotype A and between 1997 and 2003 (p < 0.01) for serotype O. Outbreaks occurred in cycles of 3-4 years for both serotypes (p < 0.05). Morbidity was not significantly different in pigs from that in cattle for serotype A-associated outbreaks (p = 0.314), but was higher in pigs than in cattle (p = 0.019) for serotype O-associated outbreaks. For both serotypes, case-fatality was higher for pigs than for cattle (p < 0.009). Temporal variation in FMD incidence provided insight into the expected evolution of FMD control for countries with similar conditions and where FMD is endemic.

Shiilegdamba, E., Perez, A.M., Thurmond, M.C., Carpenter, T.E.
Temporal-spatial epidemiology of foot-and-mouth disease outbreaks in Mongolia, 2000 - 2002.
(2008) Veterinary Research Communications, 32, pp. 201-207
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

Prior to 2000, foot-and-mouth disease (FMD) had not been observed in Mongolia since 1973; however, between April 2000 and July 2002, Mongolia reported 44 FMD outbreaks that affected cattle, sheep, goats, and camels. The objectives of this study were to describe the distributions of the 44 reported FMD outbreaks in Mongolia and to assess their spatial clustering and directions of movement. Official reports were collected to obtain the number and species of animals both affected and at risk, and the date and geographical coordinates of each outbreak. Significant global and local spatial clusters of reported FMD outbreaks were identified. Disease spread during the second epidemic moved 76 degrees northeast and the spread of the disease during the third epidemic moved 110 degrees northwest. FMD outbreaks were clustered intensely close to other FMD-positive counties. These findings can be used in the future to help plan prevention and control measures in high risk areas.

Branscum, A., Perez, A.M., Johnson, W.O., Thurmond, M.C.
Bayesian spatiotemporal analysis of foot-and-mouth disease data from the Republic of
Turkey.
(2008) Journal of Epidemiology and Infection, 136, pp. 833-842.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

A flexible hierarchical Bayesian spatiotemporal regression model for foot-and-mouth disease (FMD) was applied to data on the annual number of reported FMD cases in Turkey from 1996 to 2003. The longitudinal component of the model was specified as a latent province-specific stochastic process. This stochastic process can accommodate various types of FMD temporal profiles. The model accounted for differences in FMD occurrence across provinces and for spatial correlation. Province-level covariate information was incorporated into the analysis. Results pointed to a decreasing trend in the number of FMD cases in western Turkey and an increasing trend in eastern Turkey from 1996 to 2003. The model also identified provinces with high and with low propensities for FMD occurrence. The model's use of flexible structures for temporal trend and of generally applicable methods for spatial correlation has broad application to predicting future spatiotemporal distributions of disease in other regions of the world.

Perez, A.M., Konig, G., Späth, E., Thurmond, M.
Variation in the VP1 gene of serotype A foot-and-mouth disease virus associated with epidemiological characteristics of outbreaks in the 2001 epidemic in Argentina.
(2008) Journal of Veterinary Diagnostic Investigation, 20, pp. 433-439.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

A mixed binomial Bayesian regression model was used to quantify the relation between nucleotide differences in the VP1 gene of Foot-and-mouth disease virus (FMDV) serotype A, and epidemiologic characteristics of the outbreaks from which the viruses were obtained between January and December 2001 in Argentina. An increase in the probability of different nucleotides between isolates was associated with a longer time between isolation dates, a greater distance between isolation locations, an increase in the difference between attack rates, and an increase in the difference in outbreak durations. The farther apart the outbreak herds were in the southerly and easterly directions, the greater the difference in nucleotide changes. The model accurately predicted genetic distances of isolates obtained in 2001 compared with a 2002 isolate (P < 0.01), which suggested that the predictive modeling approach applied in the present study may be useful in understanding the epidemiology of evolution of FMDV and in forensic analysis of disease epidemics.

Estrada, C., Perez, A.M., Thurmond, M.C.
Herd reproduction ratio and time-space analysis of a foot-and-mouth disease epidemic in Peru in 2004.
(2008) Transboundary and Emerging Diseases, 55, pp. 284-292.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

The herd reproductive ratio (Rh) and spatio-temporal clustering were estimated in the 2004 foot-and-mouth disease (FMD) epidemic in Peru. The epidemic lasted 39 days and involved 26 herds. Movement of cattle was restricted, all susceptible species within a 25-km buffer zone were revaccinated, and infected animals with clinical signs of FMD were killed or destroyed to control and eradicate the disease. The Rh declined from 5.3 on the second day of the epidemic to 1.31 on the 25th day. Spatio-temporal clustering of cases was detected at a critical distance of 0.5 km and critical times of 7 and 14 days. Cases were clustered in space (P=0.006) but not in time (P=0.498). The space-time scan method detected a spatio-temporal cluster that included consecutive case numbers 13, 14 and 15, located at the temporal midpoint of the epidemic. The values estimated for Rh and the cluster analyses provide quantitative estimates of the self-limiting nature of FMD spread in a susceptible but vaccinated population.

AlKhamis, M., Perez, A.M., Yadin, H., Knowles, N.
(2009) Temporospatial clustering of foot-and-mouth disease outbreaks in Israel and Palestine, 2006-2007.
Transboundary and Emerging Diseases, 56, pp. 99-107
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.eduu
View Abstract

Foot-and-mouth disease (FMD) is endemic to the Middle East and there is a perception that political instability and limited resources have led to the uncontrolled circulation of FMD virus throughout the region. Certain aspects of FMD epidemiology in the Middle East remain unknown. The goal of this study was to identify the geographical location, temporal extent and direction of spread of clusters of 70 FMD outbreaks reported in Israel and Palestine from February 4, 2006, through July 15, 2007. The space-time permutation model of the scan statistic test detected nine significant (P < 0.1) clusters. Significant (P < 0.05) direction of spread was identified in four of the nine clusters. The Gaza Strip, where no outbreaks were reported, or a nearby location, seemed to be the origin of a cluster of outbreaks located in Hadarom (April 2007); a cluster of outbreaks centered in West Bank (February 2006) may be linked with spread from Northern Israel; a cluster in Hazafon (January 2007) seemed to have originated from nearby the Jordan borders; and a cluster located in Northern Hazafon was likely related to areas next to the Lebanon and Syrian borders. The association between the clusters in West Bank and earlier Israeli samples and between the cluster in Hazafon and Jordan was also supported (P < 0.05) by phylogenetic analysis of samples collected from the outbreaks. These results suggest that the FMD outbreaks reported in Israel and Palestine in 2006 and 2007 were likely a consequence of different epidemics associated with the circulation and spread of FMD virus strains from different regions of the Middle East.

Goal 3
Development of the next generation of control measures and strategies for their application [read more...]

Objective 3.1 Discover vaccines specifically designed for the control and eradication of the FMD virus

Pena L, Moraes MP, Koster M, Burrage T, Pacheco JM, San Segundo FD, Grubman MJ.
Delivery of a foot-and-mouth disease virus empty capsid subunit antigen with nonstructural protein 2B improves protection of swine.
(2008) Vaccine, 26 (45), pp. 5689-5699.
Plum Island Animal Disease Center, Agricultural Research Service, US Department of Agriculture, Greenport, New York 11944, USA.
Corresponding author: marvin.grubman@ars.usda.gov
View Abstract

DOCUMENT TYPE: Article
Abstract: To develop a more efficacious human adenovirus (Ad5)-vectored foot-and-mouth disease virus (FMDV) subunit vaccine (Ad5-A24) we have included coding regions for FMDV nonstructural proteins 2B and 2C. These proteins are involved in membrane re-arrangements resulting in the proliferation of cytoplasmic vesicles which serve as the sites of virus replication. Cells infected with a vector containing full-length 2B (Ad5-CI-A24-2B) had a significant increase in the number of cytoplasmic vesicles as compared to cells infected with the original vector or a vector containing full-length 2BC. Swine inoculated with Ad5-CI-A24-2B developed an enhanced FMDV-specific neutralizing antibody response as compared to animals inoculated with the original vector and showed no clinical signs of disease after challenge. In a second experiment animals vaccinated with Ad5-CI-A24-2B were not fully protected but had a more rapid and robust humoral response and two out of three pigs had delayed and less severe disease than animals in the other vaccinated groups. These results suggest that incorporation of the complete coding region of 2B into the vaccine enhances its potency and protective efficacy.

Objective 3.4 Determine scientific information to implement effective biosecurity measures

Rhyan, J., Deng, M., Wang, H., Ward, G., Gidlewski, T., McCollum, M., Metwally, S., McKenna, T., Wainwright, S., Ramirez, A., Mebus, C., and Salman, M.
Foot-and-Mouth Disease in North American bison and elk: susceptibility, intra- and interspecies transmission, clinical signs, and lesions.
(2008) Journal of Wildlife Diseases, 44 (2), pp. 269-279.
National Wildlife Research Center, Veterinary Services, Animal and Plant Health Inspection Service, US Department of Agriculture, Fort Collins, Colorado 80521, USA.
Corresponding author: jack.c.rhyan@aphis.usda.gov
View Abstract

DOCUMENT TYPE: Article
Abstract: There is limited information about the pathogenesis and epidemiology of foot-and-mouth disease (FMD) in North American bison (Bison bison) or elk (Cervus elaphus nelsoni). In these two experimental infection studies, we compared the susceptibilities of bison and elk to FMD virus (FMDV), respectively, with that of cattle; determined whether intra- and interspecies transmission could occur in bison and cattle, and elk and cattle; determined suitability of conventional available laboratory tests to detect FMDV infection in bison and elk; and investigated whether bison or elk are efficient long-term carriers of FMDV. In both studies, after a period of acclimation to the containment at Plum Island Animal Disease Center, animals were infected by intraepithelial tongue inoculation with 10,000 bovine tongue infective doses of FMDV, strain O1 Manisa. Inoculated animals were kept with contact animals; subsequently, inoculated and/or exposed contact animals were placed in rooms with unexposed animals. All bison developed oral mucosal and foot lesions similar to those of cattle. Bison developed fever, lameness, inappetence, and ptyalism. Physical examinations on bison revealed numerous small vesicles and erosions affecting tongue, gingiva, muzzle, hard and soft palates, coronary bands, and interdigital skin. Inoculated elk developed transient fever and mild focal tongue and foot lesions. Contact elk developed neither clinical signs nor gross pathologic lesions of FMD. At necropsy, lesions in bison included numerous extensive vesicles, erosions, and/or ulcers in the oral cavities, feet, and rumen pillars depending on the stage of disease. Less extensive oral, foot, and rumen lesions were present in the inoculated elk. All bison and inoculated elk developed antibodies to FMDV and were positive for FMDV by reverse transcription-polymerase chain reaction (RT-PCR). Transmission occurred between cattle and bison, and bison and bison. It did not occur between elk and cattle. Elk-to-elk transmission studies resulted in only one contact elk developing serologic evidence of a subclinical infection. Other exposed elk developed neither clinical, pathologic, virologic, nor serologic evidence of disease. FMDV was not isolated from animals past 28 days postinfection.

Thurmond, M.C., Perez, A.M.
Modeled detection time for foot-and-mouth disease (FMD) virus in bulk tank milk for FMD surveillance.
(2006) American Journal of Veterinary Research, 67, pp. 2017-2024
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

OBJECTIVE: To estimate when foot-and-mouth disease virus (FMDV) would first be detected in bulk tank milk of dairies after exposure to FMDV. SAMPLE POPULATION: Hypothetical dairy herds milking 100, 500, or 1,000 cows. PROCEDURES: For each day after herd exposure to FMDV, infection, milk yield, and virolactia were simulated for individual cows with low and high rates of intraherd transmission to estimate when a PCR assay would detect virus in bulk tank milk. Detection limits were based on assumptions for the number of virus genomes per milliliter of milk and for analytical sensitivity of a PCR assay. RESULTS: A mean of 10% of the cows was predicted to have FMD lesions from 7 to 8 days and from 13.5 to 15 days after herd exposure for herds with high and low intraherd transmission rates, respectively. Herd bulk milk volume decreased by 10% by 8.5 to 9.5 days and by 15 to 16.5 days after herd exposure for herds with high and low transmission rates, respectively. Mean times by which FMDV would be first detected in bulk milk were 2.5 days and 6.5 to 8 days after herd exposure, which were extended for 10 to 11 days and 17 to 18 days for herds with high and low transmission rates, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: PCR screening of bulk milk for FMDV would likely detect FMDV in dairy herds several days sooner than might be expected for owner reporting of clinical signs and thus should be worthy of consideration for regional, national, or global FMD surveillance.

Martinez-Lopez, B., Perez, A.M., De la Torre Reoyo, A., Sanchez-Vizcaino, J.M.
Quantitative risk assessment of foot-and-mouth disease introduction into Spain via importation of live animals.
(2008) Preventive Veterinary Medicine, 86, pp. 43-56.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.eduu
View Abstract

Spain has been a foot-and-mouth disease (FMD)-free country since 1986. However, the FMD epidemics that recently affected several European Union (EU) member countries demonstrated that the continent is still at high risk for FMD virus (FMDV) introduction, and that the potential consequences of those epidemics are socially and financially devastating. This paper presents a quantitative assessment of the risk of FMDV introduction into Spain. Results suggest that provinces in north-eastern Spain are at higher risk for FMDV introduction, that an FMD epidemic in Spain is more likely to occur via the import of pigs than through the import of cattle, sheep, or goats, and that a sixfold increase in the proportion of premises that quarantine pigs prior to their introduction into the operation will reduce the probability of FMDV introduction via import of live pigs into Spain by 50%. Allocation of resources towards surveillance activities in regions and types of operations at high risk for FMDV introduction and into the development of policies to promote quarantine and other biosecurity activities in susceptible operations will decrease the probability of FMD introduction into the country and will strengthen the chances of success of the Spanish FMD prevention program.

Goal 4
Determine social and economic impacts of new generation of improved FMD control [read more...]

Objective 4.2 Study social incentives to utilize control measures

Garabed, R.B., Johnson, W.O., Gill, J., Perez, A.M., Thurmond, M.C.
Effects of politics and economics on country-level Foot-and-Mouth-Disease status.
(2008) Journal of the Royal Statistical Society (Series A), 171, pp. 699-722.
Center for Animal Disease Modeling and Surveillance, UC Davis, One Shields Avenue, Davis, CA 95616, USA
Corresponding author: amperez@ucdavis.edu
View Abstract

Using Bayesian model averaging, we quantify associations of governance and economic health with country level presence of foot-and-mouth disease (FMD) and estimate the probability of the presence of FMD in each country from 1997 to 2005. The Bayesian model averaging accounted for countries' previous FMD status and other possible confounders, as well as uncertainty about the ‘true' model, and provided accurate predictions (90% specificity and 80% sensitivity). This model represents a novel approach to predicting FMD, and other conditions, on a global scale and in identifying important risk factors that can be applied to global policy and allocation of resources for disease control.

Goal 5
Provide evidence to inform development of policies for safe trade of animals and animal products in FMD endemic areas [read more...]