Friday, 22nd September 2017

 Virology and Microbiology

               Virus Cell Interaction. The African swine fever virus model







Yolanda Revilla







Research summary:

ASFV is a large DNA virus that infects monocytes/macrophages of different species of suids, causing the acute, economically important and frequently fatal ASF. Our group has described that ASFV, like other complex DNA viruses, deploys a variety of strategies to evade the host's defense systems, such as inflammatory and immune responses and cell death. We also demonstrated that ASFV regulates and redistributes the cellular machinery to synthesize viral proteins while impairing the production of cellular proteins. In fact, eIF4E/ 4G have been found close to viral factories, besides ribosomes, and the mitochondrial network; furthermore, phosphorylation cascades and signal transduction pathways are also handled by the virus.
Importantly, we have recently described that ASFV enters to the host cells by macropinocytosis, directly inducing actin polarization as well as EGFR, PI3K-Akt, Pak1 andRac1 activation. These pathways may activate innate host defense systems such as Toll-like receptor signaling of apoptosis or they may activate processes essential for the virus to replicate. Further characterization of the virus proteins involved in the binding and entry process will identify new pathways and virus targets for vaccine development and will also identify virus genes which may be deleted to construct attenuated ASFV strains.
Despite the notable efforts done during the last decades to obtain a preventive vaccine againstASFV infection, currently we are still far to succeed. Thus, one of our main interests is the development of a efficient vaccine against ASF. For this purpose, two approaches will be followed: 1) the rational development of ASFV deletion mutants as candidate vaccine strains, and 2) the identification of protective antigens and development of DNA vaccines. Since adjuvants are key in triggering different types of immune response, adjuvants targeted to innate immune receptors will be tested in combination with those vaccines to induce protective immune responses.



 fig01-300   fig02-300 
ASFV infection promotes cap-dependent translation. Activation of eIF4E and eIF4G during ASFV infection. ASFV promotes phosphorylation and ofeIF4E, eIF4G and the repressor of eIF4E, 4E-BP. eIF,eukaryotic translation initiation factor; 4E-BP, eIF4E binding protein, Mnk-1, mitogen activated kinase 1; ASFV, African Swine Fever Virus.   Ruffles induction upon African Swine Fever Virus Entry. Macropinocytosisendocytic pathway is used by ASFV to enter cells triggering plasma membrane protrusions that depend on extensive actin cytoskeleton restructuring as well as activation of several kinases and Rho GTPasas.
Field Emission Scanning Electron Microscopy shows ruffles induced by ASFV through which the virus (200 nm) enters into the cell.



Selected Publications:

G. Sánchez, E., Quintas, A., Pérez-Núñez, D., Nogal, M.L., Barroso, S., L. Carrascosa, A., and Revilla, Y. (2012). African Swine Fever Virus Uses Macropinocytosis to Enter Host Cells. PLoS Pathogens, 8(6): e1002754.

Jiménez, J.L., Gómez, R., Briz, V., Madrid, R, Bryszews, M., de la Mata, F.J., and Muñoz-Fernández, M.A. (2012) Carbosilanedendrimers as carriers of siRNA. J. Drug Deliv. Sci. Tech., 22: 75-82.

Briz, V., Serramía, M.J., Madrid, R., Turrin, C.O., Caminade, A.M., Majoral, J.P., and Muñoz-Fernández, M.A. (2012) Validation of a Generation 4 Phosphorus-Containing PolycationicDendrimer for Gene Delivery against HIV-1. Curr Med Chem, 19(29):5044-5051.