Thursday, 21st June 2018

 Virology and Microbiology

              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 marker vaccines that can induce protective humoral and cellular immune responses, using the pig, an important natural host, as an animal model. Some of these strategies are also being applied to the development of new vaccines against classical swine fever (CSF).

fig01-300  -------  fig02-300
Diagram showing a FMDV pentameric capsid subunit, including mutations that increase (red) or reduce (blue) the acidic pH sensitivity of viral particle. VP1 green, VP2 magenta, VP3 cian.  

Structural model for the dimer established between the N-ter of two FMDV 3A proteins. Residues participating in the hydrophobic interface, whose contribution to dimer stability has been experimentally tested, are indicated.



We are also analyzing the functional role of FMDV proteins on the 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) in cultured cells and in animal models. Special attention is being paid to the functional implications of non-structural proteins, like those from the FMDV 3AB region, in virus virulence and host range. A parallel study of the functional implications of non-coding RNA regions is also being conducted, in particular their capacity to elicit innate immune responses and their potential use as antiviral and immunomodulatory elements after delivery as synthetic RNA transcripts. Besides providing basic information on the multiplication cycle of these viruses, the results obtained are being used for the identification of antiviral targets, attenuation determinants as well as the design of new vaccine strategies. As part of these studies, we are characterizing the inhibitory effect of valproic acid on the multiplication of enveloped viruses.oltura.

Relevant publications:

  • Vázquez-Calvo, A., Saiz, J.C., Sobrino, F*. and Martín-Acebes, M.A. Inhibition of enveloped virus infection of cultured cells by valproic acid. J. Virol. 85, 1267-1274 (2011).
  • Tarradas, J., Monsó, M., Muñoz, M., Rosel, R., Fraile, L., Mora, M., Muñoz, I., Andreu, D., Sobrino, F. and Ganges, L.* Partial protection against classical swine fever virus elicited by dendrimeric vaccine-candidate peptide in domestic pigs. Vaccine 29, 4422-4429 (2011).
  • Martín-Acebes, M., Vázquez-Calvo, A, Rincón, V., Mateu; M.G. and Sobrino, F*. A single amino acid substitution in the capsid of foot-and-mouth disease virus can increase acid resistance. J. Virol. 85, 2733-2740 (2011)
  • Rodríguez-Pulido, M., Borrego, B., Sobrino, F. and Sáiz, M*. RNA structural domains in non-coding regions of foot-and-mouth disease virus genome trigger innate immunity in porcine cells and mice. J. Virol. 85, 6492-6501 (2011).
  • Rodríguez-Pulido, M., Sobrino, F., Borrego, B. and Sáiz. M*. Inoculation of newborn mice with non-coding regions of foot-and-mouth disease virus RNA can induce a rapid, solid and wide-range protection against viral infection. Antiviral Res. 92, 500-504 (2011).
  • González-Magaldi, M., Postigo, R., de la Torre, B.G., Vieira, Y.A., López-Viñas, E., Gómez-Puertas, P., Andreu, D., Kremer, L., Rosas, M. F. and Sobrino, F*. Mutations that hamper dimerization of foot-and-mouth disease virus 3A protein are detrimental for infectivity. J. Virol. 86, 11013-11023 (2012).
  • Vázquez-Calvo,A., Caridi, F., Rodriguez-Pulido, M., Borrego, B., Sáiz, F, Sobrino, F*. and Martín-Acebes, M.A. Modulation of foot-and-mouth disease virus pH threshold for uncoating correlates with differential sensitivity to inhibition of cellular Rab GTPases and decreases infectivity in vivo. J. Gen. Virol. 93:2382-2386 (2012).
  • Vázquez-Calvo, A., Sobrino, F*. and Martín-Acebes. M.A. Plasma membrane phosphatidylinositol 4, 5 bisphosphate is required for internalization of foot-and-mouth disease virus and vesicular stomatitis virus. PLoS ONE, 7(9): e45172. doi:10.1371/journal.pone.0045172 (2012). Rodríguez-Pulido, M., Martín-Acebes, M-A.,
  • Escribano-Romero, E., Blázquez A.B., Sobrino, F., Borrego, B., Sáiz, M., Saiz, J.C.* Protection against West Nile virus infection in mice after inoculation with type I interferon-inducing RNA transcripts. PLoS ONE 7(11): e49494 (2012).
  • 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).

* Corresponding author



  1. M. Sáiz, F. Sobrino, B. Borrego, M. Rodriguez, J.C. Sáiz y M.A Martín. Uso de una región no codificante del genoma del virus de la fiebre aftosa para la elaboración de un medicamento antiviral.P201130445. España (25 de marzo 2011). PCT solicitada el 25/3/2012 (PCT ES 2012/070198). CSIC-INIA.
  2. C. Cubillo, E. Blanco, J. Bárcena, F. Sobrino y D. Andreu. Peptide vaccines for the prevention of foot-and-mouth disease. P8244EP00. Patente Europea (2 de marzo de 2012). UPF, CSIC, INIA.

Doctoral Theses:

Mónica González Magaldi (2012). Caracterización de la proteína 3A del virus de la fiebre aftosa. Estudio de su dimerización, capacidad de unión a membranas y dinámica celular. Director: F. sobrino.

Angela Vázquez Calvo (2012). Estudio de los requerimientos para la entrada del virus de la fiebre aftosa en cultivos celulares y caracterización de ácido valproico como compuesto antiviral. Universidad Autónoma de Madrid. Directores: M.A. Martín Acebes y F. Sobrino (CBMSO).

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.