title: Estrogen receptor 2b deficiency impairs the antiviral response of zebrafish.
abstract: Although several studies have demonstrated the ability of some endocrine disruptive chemicals (EDCs) to alter the physiology of zebrafish, the immune-reproductive interaction has received little attention in this species. In this study, we used a homozygous line carrying an insertion of 8 amino acids in the ligand-binding domain of the estrogen receptor 2b gene (esr2b) to further understand the role of estrogen signaling on innate immunity. Adult mutant fish showed distorted sexual ratios related with alterations in testicular morphology and supraphysiological testosterone and 17β-estradiol (E2) levels. Immunity-wise, although esr2b mutant fish showed unaltered antibacterial responses, they were unable to mount an effective antiviral response upon viral challenge. RT-qPCR analysis demonstrated that mutant fish were able to induce the genes encoding major antiviral molecules, including Ifnphi1, Ifnphi2, Infphi3, Mxb and Mxc, and the negative feedback regulator of cytokine signaling Socs1. Notably, although esr2b mutant larvae showed a similar resistance to SVCV infection to their wild type siblings, waterborne E2 increased their viral susceptibility. Similarly, the exposure of adult wild type zebrafish to E2 also resulted in increased susceptibility to SVCV infection. Finally, the administration of recombinant Ifnphi1 hardly reversed the higher viral susceptibility of esr2b mutant zebrafish, suggesting that elevated socs1 levels impair Ifn signaling. All together, these results uncover an important role for E2 and Esr signaling in the fine-tuning of sexual hormone balance and the antiviral response of vertebrates.
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: López-Muñoz
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Liarte
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Gómez-González
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cabas
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Meseguer
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Alfonsa
authors.initials: A
authors.lastname: García-Ayala
authors.affiliation: Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain. Electronic address: vmulero@um.es.
authors.forename: Victoriano
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D004958:Estradiol / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000235:genetics*; D005393:Fish Diseases / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D007113:Immunity, Innate / Q000276:immunology; D007372:Interferons / Q000096:biosynthesis; D007814:Larva / Q000276:immunology; D064547:Myxovirus Resistance Proteins / Q000096:biosynthesis; D012209:Rhabdoviridae / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014733:Vibrio / Q000276:immunology*; D015027:Zebrafish / Q000235:genetics / Q000276:immunology*; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D047629:Estrogen Receptor beta; D064547:Myxovirus Resistance Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D029961:Zebrafish Proteins; C000594790:estrogen receptor 2b, zebrafish; C543714:inteferon phi2, zebrafish; C543713:interferon phi1, zebrafish; C540939:socs1a protein, zebrafish; D004958:Estradiol; D007372:Interferons
keywords: Cytokine; Evolution; Interferons; Reproductive immunology; Sexual hormones; Viral infection; Zebrafish