Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

Encinas, Paloma; García-Valtanen, Pablo; Chinchilla, Blanca; Gómez-Casado, Eduardo; Estepa, A.; Coll, Julio

doi:10.1371/journal.pone.0073553

Cited by 46 publications

(63 citation statements)

References 56 publications

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“…NFκB protein expression and nuclear translocation were visualized through whole-embryo immunofluorescence using a modified protocol from Encinas et al (26). Briefly, 3 DPF larvae were exposed to LPS (100 μg/mL) by static immersion for 2 h at 28.5°C.…”

Section: Discussionmentioning

confidence: 99%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

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Section: Discussionmentioning

confidence: 99%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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“…Many groups have been using zebrafish as a model to study fish viral response, but to date, no virus naturally infecting zebrafish has been described (Crim and Riley, 2012). However, the embryo and adult zebrafish are able to counteract model viral infections, such as spring viraemia of carp virus (Levraud et al, 2007;Encinas et al, 2013), snakehead rhabdovirus (Phelan et al, 2005) and infectious haematopoietic necrosis virus (Ludwig et al, 2011). Thus, we were interested in characterising in depth, at the cellular and transcriptomic level, whether ZFL cells had a prototypical anti-viral response and could indeed be used for immunological response studies.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish liver (ZFL) cells are able to mount an anti-viral response after stimulation with Poly (I:C)

Ruyra

Torrealba

Morera

et al. 2015

Comparative Biochemistry and Physiology Part B: Biochemistry an

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“…For example, by using high-throughput methods such as pathway-targeted microarrays and transcriptomic and proteomic analyses, many immune-and autophagy-related genes have been identified to be involved in an SVCV infection (22)(23)(24)(25). The expression of IFN could be elicited by an SVCV infection, and overexpression of IFN could significantly increase the survival of zebrafish embryos infected with SVCV (26)(27)(28).…”

mentioning

confidence: 99%

Spring Viremia of Carp Virus N Protein Suppresses Fish IFNφ1 Production by Targeting the Mitochondrial Antiviral Signaling Protein

et al. 2016

The Journal of Immunology

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For a virus to replicate efficiently, it must try and inhibit host IFN expression because IFN is an important host defense at early stages after viral infection. For aquatic viruses, the mechanisms used to escape the hosts IFN system are still unclear. In this study, we show that the N protein of spring viremia of carp virus (SVCV) inhibits zebrafish IFNφ1 production by degrading the mitochondrial antiviral signaling protein (MAVS). First, the upregulation of IFNφ1 promoter activity stimulated by polyinosinic:polycytidylic acid, retinoic acid–inducible gene I (RIG-I) or MAVS was suppressed by the SVCV infection. However, the upregulation by the downstream factor of the RIG-I–like receptor signaling pathway, TANK-binding kinase 1, was not affected. Notably, at the protein level, MAVS decreased remarkably when cells were infected with SVCV. Second, consistent with the result of the SVCV infection, overexpression of the N protein of SVCV blocked the IFNφ1 transcription activated by MAVS and downregulated MAVS expression at the protein level but not at the mRNA level. Further analysis demonstrated that the N protein targeted MAVS for K48-linked ubiquitination, which promoted the degradation of MAVS. These data indicated that fish MAVS could be degraded by the N protein of SVCV through the ubiquitin-proteasome pathway. To our knowledge, this is the first article of a fish RIG-I–like receptor pathway interfered by an aquatic virus in an ubiquitin-proteasome manner, suggesting that immune evasion of a virus also exists in lower vertebrates.

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Identification of Multipath Genes Differentially Expressed in Pathway-Targeted Microarrays in Zebrafish Infected and Surviving Spring Viremia Carp Virus (SVCV) Suggest Preventive Drug Candidates

Cited by 46 publications

References 56 publications

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Zebrafish liver (ZFL) cells are able to mount an anti-viral response after stimulation with Poly (I:C)

Spring Viremia of Carp Virus N Protein Suppresses Fish IFNφ1 Production by Targeting the Mitochondrial Antiviral Signaling Protein

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