title: Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4.
abstract: Bluetongue virus (BTV) replicates in lymphoid tissues where infected mononuclear leukocytes secrete proinflammatory and vasoactive mediators that can contribute to bluetongue (BT) pathogenesis. Using the well-characterized IFNAR(-/-) mice animal model, we have now studied the histopathology and dynamics of leukocyte populations in different target tissues (spleen, thymus, and lung) during BTV-4 infection by histological and immunohistochemical techniques. The spleen and thymus of BTV-4 infected mice showed severe lymphoid depletion on H&E stained sections. This finding was confirmed by IHC, showing moderate decreased immunopositivity against CD3 in the thymus, and scarce immunoreactivity against CD3 and CD79 in the rest of the white pulp in the spleen, together with an increase in MAC387 immunostaining. BTV-4 infection also induced the expression of active caspase-3 in the spleen, where apoptotic debris was observed by H&E. A dramatic increase in iNOS immunoreactivity associated to necrotic areas of the white pulp was observed, being less noticeable in the thymus and the lung. The induction of pro-inflammatory cytokines in tissues where BTV replicates was evaluated by measuring transcript levels by RT-qPCR. BTV-4 infection led to enhance transcription of IFN-γ, TNF, IL-6, IL-12-p40, and IL-1β mRNA in the thymus, spleen and lung, correlating with the level of virus replication in these tissues. Disease progression and pathogenesis in IFNAR(-/-) mice closely mimics hallmarks of bluetongue disease in ruminants. IFNAR(-/-) mice are a good choice to facilitate a faster advance in the field of orbiviruses.
authors.affiliation: INIA-CISA, Ctra. Algete-El Casar, Valdeolmos, 28130 Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Marín-López
authors.affiliation: Departamento de Ciencias Clínicas Veterinarias, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bermúdez
authors.affiliation: INIA-CISA, Ctra. Algete-El Casar, Valdeolmos, 28130 Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Calvo-Pinilla
authors.affiliation: INIA-CISA, Ctra. Algete-El Casar, Valdeolmos, 28130 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.affiliation: INIA-CISA, Ctra. Algete-El Casar, Valdeolmos, 28130 Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Brun
authors.affiliation: INIA-CISA, Ctra. Algete-El Casar, Valdeolmos, 28130 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ortego
mesh_terms: D000818:Animals; D001819:Bluetongue / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D001820:Bluetongue virus / Q000472:pathogenicity*; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D065288:Serogroup; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12
keywords: IFNAR(-/-) mice; bluetongue virus; cytokine; leukocyte; pathology.