{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:19:46Z","timestamp":1790662786844,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31772780"],"award-info":[{"award-number":["31772780"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFD0501300"],"award-info":[{"award-number":["2017YFD0501300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Foot and mouth disease virus (FMDV), whose transmission occurs through mucosal surfaces, can also be transmitted through aerosols, direct contact, and pollutants. Therefore, mucosal immunity can efficiently inhibit viral colonization. Since vaccine material delivery into immune sites is important for efficient oral mucosal vaccination, the M cell-targeting approach is important for effective vaccination given M cells are vital for luminal antigen influx into the mucosal lymph tissues. In this study, we coupled M cell-targeting ligand Co1 to multi-epitope TB1 of FMDV to obtain TB1-Co1 in order to improve delivery efficiency of the multi-epitope protein antigen TB1. Lactococcus lactis (L. lactis) was engineered to express heterologous antigens for applications as vaccine vehicles with the ability to elicit mucosal as well as systemic immune responses. We successfully constructed L. lactis (recombinant) with the ability to express multi-epitope antigen proteins (TB1 and TB1-Co1) of the FMDV serotype A (named L. lactis-TB1 and L. lactis-TB1-Co1). Then, we investigated the immunogenic potential of the constructed recombinant L. lactis in mice and guinea pigs. Orally administered L. lactis-TB1 as well as L. lactis-TB1-Co1 in mice effectively induced mucosal secretory IgA (SIgA) and IgG secretion, development of a strong cell-mediated immune reactions, substantial T lymphocyte proliferation in the spleen, and upregulated IL-2, IFN-\u03b3, IL-10, and IL-5 levels. Orally administered ligand-conjugated TB1 promoted specific IgG as well as SIgA responses in systemic and mucosal surfaces, respectively, when compared to orally administered TB1 alone. Then, guinea pigs were orally vaccinated with L. lactis-TB1-Co1 plus adjuvant CpG-ODN at three different doses, L. lactis-TB1-Co1, and PBS. Animals that had been immunized with L. lactis-TB1-Co1 plus adjuvant CpG-ODN and L. lactis-TB1-Co1 developed elevated antigen-specific serum IgG, IgA, neutralizing antibody, and mucosal SIgA levels, when compared to control groups. Particularly, in mice, L. lactis-TB1-Co1 exhibited excellent immune effects than L. lactis-TB1. Therefore, L. lactis-TB1-Co1 can induce elevations in mucosal as well as systemic immune reactions, and to a certain extent, provide protection against FMDV. In conclusion, M cell-targeting approaches can be employed in the development of effective oral mucosa vaccines for FMDV.<\/jats:p>","DOI":"10.3390\/v13102036","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T01:59:47Z","timestamp":1633917587000},"page":"2036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Immune Responses to Orally Administered Recombinant Lactococcus lactis Expressing Multi-Epitope Proteins Targeting M Cells of Foot-and-Mouth Disease Virus"],"prefix":"10.3390","volume":"13","author":[{"given":"Fudong","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianliang","family":"Lv","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"},{"name":"Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,9]]},"reference":[{"key":"ref_1","first-page":"9","article-title":"Foot-and-mouth disease: Host range and pathogenesis","volume":"288","author":"Alexandersen","year":"2005","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Han, L., Xin, X., Wang, H., Li, J., Hao, Y., Wang, M., Zheng, C., and Shen, C. (2018). Cellular response to persistent foot-and-mouth disease virus infection is linked to specific types of alterations in the host cell transcriptome. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-23478-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5772","DOI":"10.1016\/j.vaccine.2015.09.055","article-title":"Cross-protective efficacy of engineering serotype A foot-and-mouth disease virus vaccine against the two pandemic strains in swine","volume":"33","author":"Zheng","year":"2015","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Xie, Y., Chang, H., Li, Z., and Zhang, Y. (2020). Adenovirus-Vectored Capsid Proteins of the Serotype A Foot-and-Mouth Disease Virus Protect Guinea Pigs Against Challenge. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.01449"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Robinson, L., Knight-Jones, T., Charleston, B., Rodriguez, L., Gay, C., Sumption, K., and Vosloo, W. (2016). Global Foot-and-Mouth Disease Research Update and Gap Analysis: 7 Pathogenesis and Molecular Biology. Transbound. Emerg. Dis., 63\u201371.","DOI":"10.1111\/tbed.12520"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5044","DOI":"10.1016\/j.ygeno.2020.09.019","article-title":"SARS-CoV-2 transcriptome analysis and molecular cataloguing of immunodominant epitopes for multi-epitope based vaccine design","volume":"112","author":"Kushwaha","year":"2020","journal-title":"Genomics"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sanches, R., Tiwari, S., Ferreira, L., Oliveira, F., Lopes, M., Passos, M., Maia, E., Taranto, A., Kato, R., and Azevedo, V. (2021). Schistosoma mansoniImmunoinformatics Design of Multi-Epitope Peptide-Based Vaccine Against Using Transmembrane Proteins as a Target. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.621706"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"749","DOI":"10.4049\/jimmunol.146.2.749","article-title":"A T cell epitope in VP1 of foot-and-mouth disease virus is immunodominant for vaccinated cattle","volume":"146","author":"Collen","year":"1991","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.virol.2012.11.001","article-title":"Foot-and-mouth disease virus (FMDV) with a stable FLAG epitope in the VP1 G-H loop as a new tool for studying FMDV pathogenesis","volume":"436","author":"Lawrence","year":"2013","journal-title":"Virology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.vetmic.2007.04.030","article-title":"Heterologous expression of FMDV immunodominant epitopes and HSP70 in P. pastoris and the subsequent immune response in mice","volume":"124","author":"Su","year":"2007","journal-title":"Vet. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jviromet.2007.12.018","article-title":"Enhanced immunogenicity of multiple-epitopes of foot-and-mouth disease virus fused with porcine interferon alpha in mice and protective efficacy in guinea pigs and swine","volume":"149","author":"Du","year":"2008","journal-title":"J. Virol. Methods"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Meloen, R., and Barteling, S. (1986). An epitope located at the C terminus of isolated VP1 of foot-and-mouth disease virus type O induces neutralizing activity but poor protection. J. Gen. Virol., 289\u2013294.","DOI":"10.1099\/0022-1317-67-2-289"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rangel, G., B\u00e1rcena, J., Moreno, N., Mata, C., Cast\u00f3n, J., Alejo, A., and Blanco, E. (2021). Chimeric RHDV Virus-Like Particles Displaying Foot-and-Mouth Disease Virus Epitopes Elicit Neutralizing Antibodies and Confer Partial Protection in Pigs. Vaccines, 9.","DOI":"10.3390\/vaccines9050470"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1600-065X.2010.00970.x","article-title":"Immunology of gut mucosal vaccines","volume":"239","author":"Pasetti","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Amacker, M., Smardon, C., Mason, L., Sorrell, J., Jeffery, K., Adler, M., Bhoelan, F., Belova, O., Spengler, M., and Punnamoottil, B. (2020). New GMP manufacturing processes to obtain thermostable HIV-1 gp41 virosomes under solid forms for various mucosal vaccination routes. Npj Vaccines, 5.","DOI":"10.1038\/s41541-020-0190-9"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-3083.2009.02321.x","article-title":"Mucosally induced immunological tolerance, regulatory T cells and the adjuvant effect by cholera toxin B subunit","volume":"71","author":"Sun","year":"2010","journal-title":"Scand. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1038\/nm1213","article-title":"Mucosal immunity and vaccines","volume":"11","author":"Holmgren","year":"2005","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.jcmgh.2021.05.014","article-title":"Polycomb Repressive Complex 2 Regulates Genes Necessary for Intestinal Microfold Cell (M Cell) Development","volume":"12","author":"George","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6221","DOI":"10.1016\/j.vaccine.2008.09.061","article-title":"Functional differences between M cells and enterocytes in sampling luminal antigens","volume":"26","author":"Kyd","year":"2008","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1078\/1438-4221-00242","article-title":"Intestinal M cells and their role in bacterial infection","volume":"293","author":"Clark","year":"2003","journal-title":"Int. J. Med Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5787","DOI":"10.4049\/jimmunol.0903184","article-title":"The M cell-targeting ligand promotes antigen delivery and induces antigen-specific immune responses in mucosal vaccination","volume":"185","author":"Kim","year":"2010","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/intimm\/dxt029","article-title":"Application of an M-cell-targeting ligand for oral vaccination induces efficient systemic and mucosal immune responses against a viral antigen","volume":"25","author":"Kim","year":"2013","journal-title":"Int. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev-food-022510-133640","article-title":"Mucosal vaccination and therapy with genetically modified lactic acid bacteria","volume":"2","author":"Wells","year":"2011","journal-title":"Annu. Rev. Food Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cano-Garrido, O., Rueda, F., S\u00e0nchez-Garc\u00eda, L., Ruiz-\u00c1vila, L., Bosser, R., Villaverde, A., and Garc\u00eda-Fruit\u00f3s, E. (2014). Expanding the recombinant protein quality in Lactococcus lactis. Microb. Cell Factories, 13.","DOI":"10.1186\/s12934-014-0167-3"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4157","DOI":"10.1128\/JB.183.14.4157-4166.2001","article-title":"Design of a protein-targeting system for lactic acid bacteria","volume":"183","author":"Dieye","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1016\/S0264-410X(02)00148-2","article-title":"Effective synthetic peptide vaccine for foot-and-mouth disease in swine","volume":"20","author":"Wang","year":"2002","journal-title":"Vaccine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1128\/JVI.75.7.3164-3174.2001","article-title":"Identification of T-cell epitopes in nonstructural proteins of foot-and-mouth disease virus","volume":"75","author":"Blanco","year":"2001","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1007\/s10529-020-02900-6","article-title":"The immune response to a recombinant Lactococcus lactis oral vaccine against foot-and-mouth disease virus in mice","volume":"42","author":"Liu","year":"2020","journal-title":"Biotechnol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3109\/10837450.2013.763263","article-title":"Chitosan-based systems for intranasal immunization against foot-and-mouth disease","volume":"19","author":"Alkan","year":"2014","journal-title":"Pharm. Dev. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1128\/CMR.14.2.430-445.2001","article-title":"Vaccination strategies for mucosal immune responses","volume":"14","author":"Ogra","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7223","DOI":"10.1128\/JVI.00401-08","article-title":"Enhanced mucosal immunoglobulin A response and solid protection against foot-and-mouth disease virus challenge induced by a novel dendrimeric peptide","volume":"82","author":"Cubillos","year":"2008","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nri2322","article-title":"The regulation of IgA class switching","volume":"8","author":"Cerutti","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrmicro2384","article-title":"The role of secretory antibodies in infection immunity","volume":"8","author":"Strugnell","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nri3322","article-title":"New concepts in the generation and functions of IgA","volume":"12","author":"Pabst","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.it.2012.09.006","article-title":"Antigen sampling in the small intestine","volume":"34","author":"Schulz","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1016\/j.vaccine.2008.03.024","article-title":"Innate inflammatory responses to the Gram-positive bacterium Lactococcus lactis","volume":"26","author":"Yam","year":"2008","journal-title":"Vaccine"},{"key":"ref_37","first-page":"336","article-title":"Immunization against bacterial diseases of the intestine","volume":"31","author":"Levine","year":"2000","journal-title":"J. Pediatric Gastroenterol. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5277","DOI":"10.4049\/jimmunol.1102077","article-title":"Convergent and divergent development among M cell lineages in mouse mucosal epithelium","volume":"187","author":"Wang","year":"2011","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6110","DOI":"10.1073\/pnas.0400969101","article-title":"Intestinal villous M cells: An antigen entry site in the mucosal epithelium","volume":"101","author":"Jang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1128\/CVI.00429-09","article-title":"IgA antibody response of swine to foot-and-mouth disease virus infection and vaccination","volume":"17","author":"Pacheco","year":"2010","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Arango Duque, G., and Descoteaux, A. (2014). Macrophage cytokines: Involvement in immunity and infectious diseases. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00491"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ong, H., Tan, W., and Ho, K. (2017). Virus like particles as a platform for cancer vaccine development. PeerJ, 5.","DOI":"10.7717\/peerj.4053"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.2217\/nnm.14.187","article-title":"Recent advances in peptide-based subunit nanovaccines","volume":"9","author":"Skwarczynski","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jri.2004.06.002","article-title":"Inoculation of Lactobacillus expressing hCG beta in the vagina induces an anti-hCG beta antibody response in murine vaginal mucosa","volume":"63","author":"Yao","year":"2004","journal-title":"J. Reprod. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.molimm.2020.02.018","article-title":"Enhanced efficacy of a multi-epitope vaccine for type A and O foot-and-mouth disease virus by fusing multiple epitopes with Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA), a novel TLR4 agonist","volume":"121","author":"Lei","year":"2020","journal-title":"Mol. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Soria, I., Quattrocchi, V., Langellotti, C., P\u00e9rez-Filgueira, M., Pega, J., Gnazzo, V., Romera, S., Schammas, J., Bucafusco, D., and Di Giacomo, S. (2018). Immune Response and Partial Protection against Heterologous Foot-and-Mouth Disease Virus Induced by Dendrimer Peptides in Cattle. J. Immunol. Res., 2018.","DOI":"10.1155\/2018\/3497401"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lee, H., Piao, D., Lee, J., Choi, J., Bok, J., Cho, C., Kang, S., and Choi, Y. (2017). Artificially designed recombinant protein composed of multiple epitopes of foot-and-mouth disease virus as a vaccine candidate. Microb. Cell Factories, 16.","DOI":"10.1186\/s12934-017-0648-2"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Feng, H., McDonough, S., Fan, J., Yang, S., Zhao, X., Lu, Y., Gan, Y., Yi, X., and Chang, Y. (2017). Phosphorylated Radix Cyathulae officinalis Polysaccharides Act as Adjuvant via Promoting Dendritic Cell Maturation. Molecules, 22.","DOI":"10.3390\/molecules22010106"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/j.1365-2249.2008.03855.x","article-title":"CpG-oligodeoxynucleotides stimulate immunoglobulin A secretion in intestinal mucosal B cells","volume":"155","author":"Blaas","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S0264-410X(00)00215-2","article-title":"CpG DNA is an effective oral adjuvant to protein antigens in mice","volume":"19","author":"McCluskie","year":"2000","journal-title":"Vaccine"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1128\/jvi.71.4.2606-2614.1997","article-title":"A large-scale evaluation of peptide vaccines against foot-and-mouth disease: Lack of solid protection in cattle and isolation of escape mutants","volume":"71","author":"Taboga","year":"1997","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1128\/jvi.66.4.1835-1840.1992","article-title":"Protective immune response against foot-and-mouth disease","volume":"66","author":"McCullough","year":"1992","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1128\/JVI.02775-06","article-title":"Enhanced antiviral activity against foot-and-mouth disease virus by a combination of type I and II porcine interferons","volume":"81","author":"Moraes","year":"2007","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1089\/jir.2012.0012","article-title":"Novel antiviral therapeutics to control foot-and-mouth disease","volume":"32","author":"Dias","year":"2012","journal-title":"J. Interferon Cytokine Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2036\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:11:00Z","timestamp":1760166660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2036"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,9]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["v13102036"],"URL":"https:\/\/doi.org\/10.3390\/v13102036","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,9]]}}}