title: Neuroinvasion of the highly pathogenic influenza virus H7N1 is caused by disruption of the blood brain barrier in an avian model.
abstract: Influenza A virus (IAV) causes central nervous system (CNS) lesions in avian and mammalian species, including humans. However, the mechanism used by IAV to invade the brain has not been determined. In the current work, we used chickens infected with a highly pathogenic avian influenza (HPAI) virus as a model to elucidate the mechanism of entry of IAV into the brain. The permeability of the BBB was evaluated in fifteen-day-old H7N1-infected and non-infected chickens using three different methods: (i) detecting Evans blue (EB) extravasation into the brain, (ii) determining the leakage of the serum protein immunoglobulin Y (IgY) into the brain and (iii) assessing the stability of the tight-junction (TJ) proteins zonula occludens-1 and claudin-1 in the chicken brain at 6, 12, 18, 24, 36 and 48 hours post-inoculation (hpi). The onset of the induced viremia was evaluated by quantitative real time RT-PCR (RT-qPCR) at the same time points. Viral RNA was detected from 18 hpi onward in blood samples, whereas IAV antigen was detected at 24 hpi in brain tissue samples. EB and IgY extravasation and loss of integrity of the TJs associated with the presence of viral antigen was first observed at 36 and 48 hpi in the telencephalic pallium and cerebellum. Our data suggest that the mechanism of entry of the H7N1 HPAI into the brain includes infection of the endothelial cells at early stages (24 hpi) with subsequent disruption of the TJs of the BBB and leakage of virus and serum proteins into the adjacent neuroparenchyma.
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Aida J
authors.initials: AJ
authors.lastname: Chaves
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Júlia
authors.initials: J
authors.lastname: Vergara-Alert
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Busquets
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Valle
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rivas
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain; Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramis
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain; Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Barcelona, Spain.
authors.forename: Ayub
authors.initials: A
authors.lastname: Darji
authors.affiliation: Centre de Recerca en Sanitat Animal (CReSA), UAB-IRTA, Campus de la Universitat Autònoma de Barcelona, Barcelona, Spain; Departament de Sanitat i Anatomia Animals, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Majó
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000821:virology*; D001927:Brain Diseases / Q000503:physiopathology* / Q000821:virology*; D002645:Chickens / Q000821:virology; D004195:Disease Models, Animal; D057916:Influenza A Virus, H7N1 Subtype / Q000276:immunology / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000503:physiopathology / Q000821:virology*; D012367:RNA, Viral / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012367:RNA, Viral