title: Zebra Fish Lacking Adaptive Immunity Acquire an Antiviral Alert State Characterized by Upregulated Gene Expression of Apoptosis, Multigene Families, and Interferon-Related Genes.
abstract: To investigate fish innate immunity, we have conducted organ and cell immune-related transcriptomic as well as immunohistologic analysis in mutant zebra fish (Danio rerio) lacking adaptive immunity (rag1-/-) at different developmental stages (egg, larvae, and adult), before and after infection with spring viremia carp virus (SVCV). The results revealed that, compared to immunocompetent zebra fish (rag1+/+),rag1-/-acquired increased resistance to SVCV with age, correlating with elevated transcript levels of immune genes in skin/fins and lymphoid organs (head kidney and spleen). Gene sets corresponding to apoptotic functions, immune-related multigene families, and interferon-related genes were constitutively upregulated in uninfected adultrag1-/-zebra fish. Overexpression of activated CASPASE-3 in different tissues before and after infection with SVCV further confirmed increased apoptotic function inrag1-/-zebra fish. Concurrently, staining of different tissue samples with a pan-leukocyte antibody marker showed abundant leukocyte infiltrations in SVCV-infectedrag1-/-fish, coinciding with increased transcript expression of genes related to NK-cells and macrophages, suggesting that these genes played a key role in the enhanced immune response ofrag1-/-zebra fish to SVCV lethal infection. Overall, we present evidence that indicates thatrag1-/-zebra fish acquire an antiviral alert state while they reach adulthood in the absence of adaptive immunity. This antiviral state was characterized by (i) a more rapid response to viral infection, which resulted in increased survival, (ii) the involvement of NK-cell- and macrophage-mediated transcript responses rather than B- and/or T-cell dependent cells, and (iii) enhanced apoptosis, described here for the first time, as well as the similar modulation of multigene family/interferon-related genes previously associated to fish that survived lethal viral infections. From this and other studies, it might be concluded that some of the characteristics of mammalian trained immunity are present in lower vertebrates.
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: García-Valtanen
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martínez-López
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca , Murcia , Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: López-Muñoz
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bello-Perez
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: Regla M
authors.initials: RM
authors.lastname: Medina-Gali
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: María Del Mar
authors.initials: MD
authors.lastname: Ortega-Villaizán
authors.affiliation: Instituto de Investigaciones Marinas (IIM), Consejo Superior de Investigaciones Científicas (CSIC) , Vigo , Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Varela
authors.affiliation: Instituto de Investigaciones Marinas (IIM), Consejo Superior de Investigaciones Científicas (CSIC) , Vigo , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Figueras
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca , Murcia , Spain.
authors.forename: Víctoriano
authors.initials: V
authors.lastname: Mulero
authors.affiliation: Instituto de Investigaciones Marinas (IIM), Consejo Superior de Investigaciones Científicas (CSIC) , Vigo , Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Novoa
authors.affiliation: Departamento de Bioquímica, Universidad Miguel Hernández de Elche (UMH) , Alicante , Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Estepa
authors.affiliation: Departamento de Biotecnología, Instituto Nacional Investigación y Tecnología Agraria y Alimentaria (INIA) , Madrid , Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Coll
keywords: antiviral alert state; multigene families and apoptosis in resistance to viral infections; spring viremia carp viral infections; trained immunity NK/macrophages in fish; zebra fish rag1−/− adaptive deficient mutants