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Fish are the phylogenetically oldest vertebrate group with an immune system with clear similarities to the immune system of mammals. However, it is an actual matter of fact that the current knowledge of the fish immune system seems to lack the key piece to complete the puzzle.

In 1953 Nelson described a new role of human red blood cells (RBCs) which would go beyond the simple transport of O2 to the tissues. This new role, involved in the defence against microbes, described the antibody and complement-dependent binding of microbial immune complexes to RBCs. Regardless of the importance of this finding in the field of microbial infection, this phenomenon has been poorly evaluated. Just recently, a set of biological processes relevant to immunity have been described in the RBCs of a diverse group of organisms, which include: pathogen recognition, pathogen binding and clearance and cytokines production.

Furthermore, it has been demonstrated that nucleated erythrocytes from fish and avian species develop specific responses to different pathogen associated molecular patterns and produce soluble factors that modulate leukocyte activity.

In the light of these pieces of evidences, and in an attempt to improve the knowledge of the immune mechanism(s) responsible for fish protection against viral infections, we raised the question: could nucleated fish erythrocytes be the key mediators of the antiviral responses? To answer this question we decided to focus our work on the evaluation of the crosstalk between red and white blood cells in the scenario of fish viral infections and prophylaxis. For that we chose a working model composed of the rainbow trout, the viral haemorrhagic septicaemia virus (VHSV) and the glycoprotein G of VHSV (GVHSV), the antigen encoded by this DNA vaccine.


Recent results demonstrate the involvement of nucleated rainbow trout erythrocytes in the innate and adaptive immune response of fish to viruses and in response to DNA vaccines.

Constitutive expression of Mx antiviral protein in rainbow trout nucleated RBCs. Immunofluorescence images of Mx protein expression in nucleated RBCs. FITC: Mx protein expression; DAPI: nuclei.


María del Mar Ortega-Villaizán Romo


Verónica Chico Gras


Iván Nombela Díaz

Sara Puente Marín


Maria Elizabhet Salvador Mira


Remedios Torres Montero

Efrén Lucas Mañoguil


  1. Front. Immunol. 2018. 9:2477. doi: 10.3389/fimmu.2018.02477. Rainbow Trout Erythrocytes ex vivo Transfection With a DNA Vaccine Encoding VHSV Glycoprotein G Induces an Antiviral Immune Response. Puente-Marin S, Nombela I, Chico V, Ciordia S, Mena MC, Coll J, Mercado L, Ortega-Villaizan M.
  2. PLoS Pathog. 2018 Apr 26;14(4):e1006910. doi: 10.1371/journal.ppat.1006910. eCollection 2018 Apr. PubMed PMID: 29698529. Nucleated red blood cells: Immune cell mediators of the antiviral response. Nombela I, Ortega-Villaizan MDM.
  3. Cells. 2018 Apr 19;7(4). pii: E31. doi: 10.3390/cells7040031. PubMed PMID: 29671811. Shape-Shifted Red Blood Cells: A Novel Red Blood Cell Stage? Chico V, Puente-Marin S, Nombela I, Ciordia S, Mena MC, Carracedo B, Villena A, Mercado L, Coll J, Ortega-Villaizan MDM.
  4. Genes (Basel). 2018 Apr 9;9(4). pii: E202. doi: 10.3390/genes9040202. PubMed PMID: 29642539. In Silico Functional Networks Identified in Fish Nucleated Red Blood Cells by Means of Transcriptomic and Proteomic Profiling. Puente-Marin S, Nombela I, Ciordia S, Mena MC, Chico V, Coll J, Ortega-Villaizan MDM.
  5. F1000Res. 2017 Nov 6 [revised 2018 Jan 1];6:1958. doi: 10.12688/f1000research.12985.2. eCollection 2017. PubMed PMID:29527292. Nombela I, Puente-Marin S, Chico V, Villena AJ, Carracedo B, Ciordia S, Mena MC, Mercado L, Perez L, Coll J, Estepa A, Ortega-Villaizan MDM. Identification of diverse defense mechanisms in rainbow trout red blood cells in response to halted replication of VHS virus. Version 2.
  6. F1000Res. 2017 Nov 7 [revised 2017 Jan 1];6:1968. doi: 10.12688/f1000research.12994.2. eCollection 2017. PubMed PMID: 29333244. Nombela I, Carrion A, Puente-Marin S, Chico V, Mercado L, Perez L, Coll J, Ortega-Villaizan MDM. Infectious pancreatic necrosis virus triggers antiviral immune response in rainbow trout red blood cells, despite not being infective. Version 2.
  7. Book “Immune Response Activation”. Edited by Guy Huynh Thien Duc, InTechOpen. In Proof editing. Nucleated Red Blood Cells Contribute to the Host Immune Response against Pathogens. Chico V, Nombela I, Puente-Marín S, ORTEGA-VILLAIZAN M.


  1. Fish Shellfish Immunol. 2018 Nov;82:514-521. doi: 10.1016/j.fsi.2018.08.056. Epub 2018 Aug 29. PubMed PMID: 30170110. Chromatin immunoprecipitation and high throughput sequencing of SVCV-infected zebrafish reveals novel epigenetic histone methylation patterns involved in antiviral immune response. Medina-Gali R, Belló-Pérez M, Martínez-López A, Falcó A, Ortega-Villaizan MM, Encinar JA, Novoa B, Coll J, Perez L.
  2. Dev Comp Immunol. 2018 Jul;84:307-314. doi: 10.1016/j.dci.2018.02.019. Epub 2018 Mar 7. PubMed PMID: 29524446. M Medina-Gali R, Ortega-Villaizan MDM, Mercado L, Novoa B, Coll J, Perez L. Beta-glucan enhances the response to SVCV infection in zebrafish.
  3. Vaccine. 2017 Jun 27;35(30):3691-3699. doi: 10.1016/j.vaccine.2017.05.073. Epub 2017 Jun 1. PubMed PMID: 28579234. Protective immunity against Megalocytivirus infection in rock bream (Oplegnathus fasciatus) following CpG ODN administration. Jung MH, Lee J, Ortega-Villaizan M, Perez L, Jung SJ.
  4. Front Immunol. 2017 Feb 13;8:121. doi: 10.3389/fimmu.2017.00121. eCollection 2017. Erratum in: Front Immunol. 2017 Jun 13;8:668. PubMed PMID: 28243233. Zebra Fish Lacking Adaptive Immunity Acquire an Antiviral Alert State Characterized by Upregulated Gene Expression of Apoptosis, Multigene Families, and Interferon-Related Genes. García-Valtanen P, Martínez-López A, López-Muñoz A, Bello-Perez M, Medina-Gali RM, Ortega-Villaizán MD, Varela M, Figueras A, Mulero V, Novoa B, Estepa A, Coll J.
  5. Mol Immunol. 2016 Feb;70:118-24. doi: 10.1016/j.molimm.2015.10.008. Epub 2016 Jan 4. Review. PubMed PMID: 26759988. Development of new therapeutical/adjuvant molecules by pepscan mapping of autophagy and IFN inducing determinants of rhabdoviral G proteins. Ortega-Villaizan M, Chico V, Martinez-Lopez A, Garcia-Valtanen P, Coll JM,Estepa A.
  6. Autophagy. 2014 Sep;10(9):1666-80. doi: 10.4161/auto.29557. Epub 2014 Jul 16. PubMed PMID: 25046110; PubMed Central PMCID: PMC4206542. Autophagy-inducing peptides from mammalian VSV and fish VHSV rhabdoviral G glycoproteins (G) as models for the development of new therapeutic molecules. García-Valtanen P, Ortega-Villaizán Mdel M, Martínez-López A, Medina-Gali R, Pérez L, Mackenzie S, Figueras A, Coll JM, Estepa A.
  7. Vaccine. 2012 Sep 7;30(41):5983-90. doi: 10.1016/j.vaccine.2012.07.013. Epub 2012 Jul 20. PubMed PMID: 22824344. Ex vivo transfection of trout pronephros leukocytes, a model for cell culture screening of fish DNA vaccine candidates. Ortega-Villaizan M, Martinez-Lopez A, Garcia-Valtanen P, Chico V, Perez L, Coll JM, Estepa A.
  8. Vaccine. 2011 Jan 17;29(4):737-43. doi: 10.1016/j.vaccine.2010.11.021. Epub 2010 Nov 21. PubMed PMID: 21095250. In vitro analysis of the factors contributing to the antiviral state induced by a plasmid encoding the viral haemorrhagic septicaemia virus glycoprotein G in transfected trout cells. Ortega-Villaizan M, Chico V, Martinez-Lopez A, Falco A, Perez L, Coll JM, Estepa A.
  9. J Virol. 2010 Jul;84(14):7140-50. doi: 10.1128/JVI.00023-10. Epub 2010 May 12. PubMed PMID: 20463070; PubMed Central PMCID: PMC2898232. Pepscan mapping of viral hemorrhagic septicemia virus glycoprotein G major lineal determinants implicated in triggering host cell antiviral responses mediated by type I interferon. Chico V, Martinez-Lopez A, Ortega-Villaizan M, Falco A, Perez L, Coll JM, Estepa A.
  10. Mol Immunol. 2009 May;46(8-9):1710-7. doi: 10.1016/j.molimm.2009.02.006. Epub 2009 Mar 9. PubMed PMID: 19272649. The rainbow trout TLR9 gene and its role in the immune responses elicited by a plasmidencoding the glycoprotein G of the viral haemorrhagic septicaemia rhabdovirus (VHSV). Ortega-Villaizan M, Chico V, Falco A, Perez L, Coll JM, Estepa A.


ERC Starting Grant 2014. Proyecto: BloodCellsCrosstalk. “The Crosstalk Between Red and White Blood Cells: The case of fish”. GA639249. European Commission.