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BLOODCELLSCROSSTALK Report Summary

Project ID: 639249
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - BLOODCELLSCROSSTALK (The Crosstalk Between Red And White Blood Cells: The Case Of Fish)

Reporting period: 2015-04-01 to 2016-09-30

Summary of the context and overall objectives of the project

What is the issue being addressed?

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 has 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 evidence, 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 project on the evaluation of the crosstalk between red and white blood cells in the scenario of fish viral infections and prophylaxis. For that a working model composed of the rainbow trout and the viral haemorrhagic septicaemia virus (VHSV) was chosen, being the objectives of the project to evaluate: i) the implication trout RBCs in the clearance of VHSV, and ii) the involvement of RBCs in the blood transportation of the glycoprotein G of VHSV (GVHSV), the antigen encoded by the DNA vaccine.

Why is it important for society?

The results obtained from this project will have a strong impact in the field of fish immunology, since they will contribute to understand the function of the RBCs in fish in relation to viral infections and DNA vaccinations. This will allow the design of novel vaccines and therapies to reinforce fish immunity and to find novel drug delivery systems. Both will have a considerable impact on the aquaculture industry, since they will permit the production of healthier fish, leading to an increased and eco-sustainable aquaculture. And, on the other hand, the results could be translated to humans, and they will help to discover new roles for RBCs in mammals.

What are the overall objectives?

A great deal of the success of a vaccine in piscine species depends on the knowledge of the fish immune system. For that, the global objective of the present project is to elucidate the role of the nucleated fish RBCs in the immune response to viral infections and related DNA vaccines. Next specific interdisciplinary objectives, comprising the fields of immunology, virology, genomics, transcriptomics and proteomics, are being addressed:

1.-Evaluate the implication of trout RBCs in VHSV binding, antiviral signalling and viral clearance, comprising: i) in vitro characterization of the association between VHSV infected trout RBCs and trout leukocytes; ii) characterization of the complement pathways involved in RBCs/VHSV immune adherence; iii) involvement of RBCs in the blood clearance of VHSV virus after rainbow trout VHSV infection; and iv) characterization of the immune system receptor- response networks implicated in the RBCs response to VHSV infection, by means of transcriptome and proteome evaluation.

2.- Involvement of trout RBCs in the blood transportation of the glycoprotein G of VHSV (GVHSV), the antigen encoded by the DNA vaccine against VHSV, in order to demonstrate the implication of trout RBCs on the protection conferred by the DNA vaccine, by means of: i) in vitro characterization of the immune system networks implicated in the RBCs response to GVHSV gene transfection by transcriptome and proteome analysis; and ii) in vivo involvement of RBCs in the transportation of the GVHSV DNA vaccine and evaluation of the crosstalk between GVHSV transfected trout RBCs and trout leukocytes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the first reporting period, we have started up the laboratory, acquired the equipment, hired the personnel and carried out the tasks planned in the working plan, with a few deviations from the initial plan due to requirements driven by the obtained results.
From the overall tasks described in the DoA, we have carried out during this period the study of the implication of trout RBCs in the immune response to viral infections, by means of proteomic evaluation. As well, we have evaluated the crosstalk between red blood cells (RBCs) and leukocytes in the scenario of fish viral infections. The work carried out includes objective 1, tasks 1.1, 1.2, 1.3 and 1.4, which have been partly achieved and are on-going. On the other hand, we have prioritized to start in this reporting period with objective 2, motivated by the results obtained in objective 1, in order to evaluate at the same time the implication of trout RBCs in the immune response to DNA vaccines with the viral antigen as well as to the virus itself. Therefore, task 2.1, which includes the transcriptomic evaluation of red blood cells after DNA vaccination, has been partly achieved in this reporting period and is still on-going.
The results obtained during the first reporting period unveils a previously unobserved but important function for fish nucleated RBCs in the immune protein contribution to innate immune defences against viral aggression. The results showed that trout RBCs might have the capacity of inactivating internalized VHSV virus by means of endogenous antiviral proteins. Besides, RBCs-stimulated cytokines might be implicated in the modulation of other immune cells, and/or in the inflammatory response. Moreover, the results suggest that RBCs may act as Antigen Presenting Cells (APCs) and participate in the adaptive immunity response against viral infections. In addition, the RBCs immune response to the DNA vaccine encoding the viral antigen showed an innate immune response mediated by chemokines, interferon stimulated proteins and antimicrobial peptides.
The obtained results will be deeply explained in the scientific report of the 30th month.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Until now, the most significant advance of this project has been the finding of the implication of trout RBCs as mediators of the antiviral innate and adaptive immune response. We have seen that fish nucleated RBCs are able to produce antiviral proteins when exposed to a viral infection or immunized with a DNA vaccine encoding the viral antigen, therefore they appear to behave as their blood counterparts, the leukocytes. For that reason, the recognition of body circulating viruses and the subsequent generation of immune defences by RBCs may largely contribute to the survival of the host, given the large volume of RBCs and its rapid and wide distribution to the whole body. Consequently, this findings will allow the identification and design of new targets for antiviral therapies, with its corresponding positive impact on the aquaculture industry. The results could be extrapolated to humans, and therefore help to discover new roles for RBCs in mammals.

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