Cabecera lazomsalas2019 11 08 CBMSO CSIC UAM

Wednesday, 20th November 2019

New strategies for prevention and control of viral diseases: foot-and-mouth disease virus as a model



Francisco Sobrino




Research summary:

Foot-and-mouth disease virus (FMDV) is one of the major concerns for animal health. It is also an interesting model system for understanding the interactions of a highly variable virus and its natural hosts and the implications of these interactions on disease control. We are working in the development of new FMDV peptide marker vaccines that can induce protective humoral and cellular immune responses, using pig and cattle, important domestics hosts, as animal models. We have also analyzed the functional role of FMDV proteins on the viral particle stability and internalization, the replication cycle and the mechanisms mediating the pathogenesis of FMDV and other related viruses causing vesicular diseases, such as swine vesicular disease virus (SVDV), and vesicular stomatitis virus (VSV). Special attention has been paid to the functional implications of nonstructural proteins in virus virulence and host range. The role of different cellular lipids in the multiplication of these and other viruses such as West Nile virus (WNV), responsible for an important zoonosis, have also been addressed. As part of these studies, we have continued collaborating in the characterization of the inhibitory effect of valproic acid and other antiviral compounds targeting cellular metabolism such as lauryl gallate on the multiplication of FMDV and of other enveloped viruses, like African swine fever virus (ASFV) and type I herpesvirus.


figure 1


In a second line of research, Margarita Sáiz undertakes the analysis of the interplay between FMDV and the innate immunity system. With the aim of unveiling the molecular mechanisms exerted by FMDV for immune evasion, the role of the two virally-encoded proteases is being studied. We have shown that the FMDV Leader protease targets innate immune sensor LGP2 for cleavage, resulting in lower levels of IFN-β and antiviral activity. The interference of the proteases with different signaling routes triggered by viral sensors and their interaction with a variety of immune effectors as potential targets for viral antagonism are being analyzed.


figure 2


On the other hand, the biotherapeutic applications of synthetic non-coding RNAs derived from the viral genome, and known to elicit a broad spectrum antiviral activity, is being explored. We have shown that RNA delivery enhanced the specific B- and T-cell mediated immune responses elicited by a conventional FMD vaccine, increasing the rate of protection against viral challenge. The activity of these molecules in livestock species is being analyzed to assess their biotechnological potential for the development of new antiviral molecules and vaccine adjuvants.



Relevant publications:

  • Borrego, B., Rodríguez-Pulido, B., Mateos, F., de la Losa, N., Sobrino, F. and Sáiz*, M. Delivery of synthetic RNA can enhance the immunogenicity of vaccines against foot-and-mouth disease virus (FMDV) in mice. Vaccine. 40, 4375-4381 (2013).
  • Sanchez-Aparicio, M.T., Rosas, M.F. and Sobrino, F*. Characterization of a nuclear localization signal in the foot-and-mouth disease virus polymerase. Virology 444, 203-210 (2013).
  • Blanco, E., Cubillos, C., Moreno, N., Bárcena, J., de la Torre, B.G., Andreu and Sobrino, F*. B epitope multiplicity/ and B/T epitope orientation influence immunogenicity of foot-and-mouth disease peptide vaccines. Clin. Dev. Immunol. 2013:475960 (2013).
  • Vazquez-Calvo, A. Caridi, F. Sobrino*, F. and Martín-Acebes, M.A. An increase in acid resistance of foot-and-mouth disease virus capsid is mediated by a tyrosine substitution of the VP2 histidine previously associated with VP0 cleavage. J. Virol. 88, 3039-3042 (2014).
  • Martín-Acebes, M.A., Merino-Ramos, T., Blázquez, A-B., Casas, J., Escribano-Romero, E., Sobrino, F*. and Saiz, J.C*. The Composition of West Nile virus Lipid Envelope Unveils a Role of Sphingolipid Metabolism on Flavivirus Biogenesis J. Virol. 88(20), 12041-54 (2014).
  • González-Magaldi, M., Martín-Acebes, M., Kremer, L. and Sobrino, F*. Membrane topology and cellular dynamics of foot-and-mouth disease virus 3A protein. PLoS ONE. 9(10): e106685. (2014).
  • Caridi, F., Vázquez-Calvo, A., Sobrino, F*. and Martín-Acebes, M.A. The pH stability of foot-and-mouth disease virus particles is modulated by residues Located at the pentameric interface and in the N terminus of VP3. J. Virol. (2015).
  • Borrego, B., Rodríguez-Pulido, M., Revilla, C., Álvarez, B., Sobrino F., Domínguez, J. and Sáiz, M*. Synthetic RNAs mimicking structural domains in the foot-and-mouth disease virus (FMDV) genome elicit a broad innate immune response in porcine cells triggered by RIG-I and TLR activation. Viruses 7, 3954-3973. doi:10.3390/v7072807 (2015).
  • Martin-Acebes, M.A., Gabandé-Rodríguez, E., García-Cabrero, A.M., Sánchez, M.P., Ledesma, M.D., Sobrino, F*. and Saiz, J.C.* Host Sphingomyelin Modulates West Nile Virus Infection in vivo. J. Lipid. Res. 57, 422-32. doi: 10.1194/jlr.M064212 (2016).
  • Blanco E.*, Guerra, G., de la Torre, B.G., Defaus, S., Andreu, D*. and Sobrino, F*. Full protection of swine against foot-and-mouth disease challenge by a bivalent B-cell epitope dendrimer peptide. Antiviral Res. 129, 74-80. doi: 10.1016/j.antiviral.2016.03.005 (2016).
  • The amino acid substitution Q65H in the 2C protein of swine vesicular disease virus confers resistance to Golgi disrupting drugs. Vázquez-Calvo, A., Caridi, F., González-Magaldi, M., Saiz, J.C. Sobrino, F*. and Martín-Acebes, M.A.*. Frontiers Microbiol. 7:612. doi: 10.3389/fmicb.2016.00612 (2016).
  • Borrego, B., Blanco, E., Rodríguez Pulido, M., Mateos, F., Lorenzo, G., Cardillo, S., Smitsaart, E., Sobrino, F. and Sáiz, M. (2017) Combined administration of synthetic RNA and a conventional vaccine improves immune responses and protection against foot-and-mouth disease virus in swine. Antiviral Res. 142, 30-36.doi: 10.1016/j.antiviral.2017.03.009.
  • Caridi, F., Vázquez-Calvo, A., Borrego, B., McCullough, K., Summerfield, A., Sobrino, F. and Martín-Acebes, M.A. (F. Sobrino, corresponding author) (2017) Preserved immunogenicity of an inactivated vaccine based on foot-and-mouth disease virus particles with improved stability. Vet. Microbiol. 203, 275 - 279.doi: 10.1016/j.vetmic.2017.03.
  • Bohórquez, J.A., Defaus, S., Muñoz-González, S., Perez-Simó, M., Rosell, R., Fraile, L., Sobrino, F., Andreu, D. and Ganges, L. (2017) A bivalent dendrimeric peptide bearing a T-cell epitope from foot-and-mouth disease virus protein 3A improves humoral response against classical swine fever virus. Virus Res. 238, 8-12.doi: 10.1016/j.virusres.2017.05.020.
  • Soria, I., Quattrocchi, V., Langellotti, C., Gammella, M., Digiacomo, S., Garcia de la Torre. B., Andreu, D., Montoya, M., Sobrino, F., Blanco, E. and Zamorano, P. (F. Sobrino, corresponding author). (2017) Dendrimeric peptides can confer protection against foot-and-mouth disease virus in cattle. PLoS ONE 12 (9): e0185184.doi: 10.1371/journal.pone.0185184.
  • Blanco, E., Andreu, D. and Sobrino, F. (2017) Peptide vaccines against foot-and-mouth disease virus. In Sobrino, F. and Domigo, E. (eds.) Foot and mouth disease virus: current research and emerging trends. Caister Academic Press, Norfolk, UK. pp.317-332.doi: 10.21775/9781910190517.15.
  • Rodríguez Pulido, M. and Sáiz, M. (2017) Molecular mechanisms of foot-and-mouth disease virus targeting the host antiviral response. Front. Cell .Infect. Microbiol. 7:252.doi: 10.3389/fcimb.2017.00252.
  • Soria, I., Quattrocchi, V., Langellotti, C., Pérez Filgueira, M., Romera, S., Schammas, J., Buscafuco, D., Garcia de la Torre, B., Andreu, D., Sobrino, F., Blanco, E. and Zamorano, P. (F. Sobrino, corresponding author) (2018) Immune response and partial protection against heterologous foot-and-mouth disease virus induced by dendrimer peptides in cattle. J. Immunol. Res.doi:10.1155/2018/3497401.
  • Rodríguez Pulido, M., del Amo, L., Sobrino, F. and Sáiz, M. (2018) Synthetic RNA derived from the foot-and-mouth disease virus genome elicits antiviral responses in bovine and porcine cells through IRF3 activation. Vet. Microbiol. 221, 8-12.doi: 10.1016/j.vetmic.2018.05.015.
  • Rodríguez Pulido, M., Sánchez-Aparicio, M.T., Martínez-Salas, E., García-Sastre, A., Sobrino, F. and Sáiz, M. (2018) Innate immune sensor LGP2 is cleaved by the leader protease of foot-and-mouth disease virus. PLoS Pathog. 14(6):e1007135.doi: 10.1371/journal.ppat.1007135.
  • de la Higuera, I., Ferrer-Orta, C.; Moreno, E., De Ávila, A., Soria, M.E., Kamlendra, S., Caridi, F., Sobrino, F., Sarafianos, C., Perales, C., Verdaguer, N. and Domingo, E. (2018) Contribution of a multifunctional polymerase region of foot-and-mouth disease virus to lethal mutagenesis. J. Virol. 92:e01119-18.doi: 10.1128/JVI.01119-18.

* Corresponding author



Edited books:

  • Sobrino, F. and Domingo, E. (eds) (2017). Foot and mouth disease virus: current research and emerging trends. Caister Academic Press, Norfolk, UK. ISBN: 978-1-910190-51-7 (paperback); 978-1-910190-52-4 (ebook).




  • Vacunas peptídicas para la prevención de la fiebre aftosa. David Andreu, Juan Bárcena del Riego, Esther Blanco, Carolina Cubillos, Beatriz García de la Torre, Marta Monsó, Francisco Sobrino. P20130101063. Argentina (03/04/2013).
  • Peptide vaccines for the prevention of foot-and-mouth disease. David Andreu, Juan Bárcena del Riego, Esther Blanco, Carolina Cubillos, Beatriz García de la Torre, Marta Monsó, Francisco Sobrino.P. number: 2013800289123. P.R.China (01/12/2014).
  • Use of esters derived from gallic acid as antivirals. P. de León, A. L. Carrascosa, M.J. Bustos, F. Sobrino. E. Torres, R. Cañas. Patente ES1641.1421 (12-11-2018).



Doctoral Theses:

  • Yuri A. Vieira (2015). Contribuciones al estudio de la funcionalidad de las proteínas no estructurales del virus de la fiebre aftosa. Universidad Autónoma de Madrid. Directores: M.F. Rosas y F. Sobrino.
  • Flavia Caridi (2017). Bases Moleculares de la estabilidad de la cápsida de los aftovirus. Universidad Autónoma de Madrid. Directores: F. Sobrino y M.A. Martín Acebes. Sobresaliente “Cum Laude”.

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