title: Neuropathology of H5N1 virus infection in ferrets.
abstract: Highly pathogenic H5N1 virus remains a potential threat to humans. Over 289 fatalities have been reported in WHO confirmed human cases since 2003, and lack of effective vaccines and early treatments contribute to increasing numbers of cases and fatalities. H5N1 encephalitis is a recognized cause of death in Vietnamese cases, and brain pathology is described in other human cases and naturally infected animals. However, neither pathogenesis of H5N1 viral infection in human brain nor post-infection effects in survivors have been fully investigated. We report the brain pathology in a ferret model for active infection and 18-day survival stages. This model closely resembles the infection pattern and progression in human cases of influenza A, and our report is the first description of brain pathology for longer term (18-day) survival in ferrets. We analyzed viral replication, type and severity of meningoencephalitis, infected cell types, and cellular responses to infection. We found viral replication to very high titers in ferret brain, closely correlating with severity of meningoencephalitis. Viral antigens were detected predominantly in neurons, correlating with inflammatory lesions, and less frequently in astrocytes and ependymal cells during active infection. Mononuclear cell infiltrates were observed in early stages predominantly in cerebral cortex, brainstem, and leptomeninges, and less commonly in cerebellum and other areas. Astrogliosis was mild at day 4 post-infection, but robust by day 18. Early and continuous treatment with an antiviral agent (peramivir) inhibited virus production to non-detectable levels, reduced severity of brain injury, and promoted higher survival rates.
authors.affiliation: Galveston National Laboratory, Sealy Vaccine Center and Institute for Human Infections and Immunity, Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, TX 77555-0609, USA.
authors.forename: Bi-Hung
authors.initials: BH
authors.lastname: Peng
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Yun
authors.forename: Olga
authors.initials: O
authors.lastname: Chumakova
authors.forename: Michele
authors.initials: M
authors.lastname: Zacks
authors.forename: Gerald
authors.initials: G
authors.lastname: Campbell
authors.forename: Jeanon
authors.initials: J
authors.lastname: Smith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Seth
authors.initials: S
authors.lastname: Linde
authors.forename: Jenna
authors.initials: J
authors.lastname: Linde
authors.forename: Slobodan
authors.initials: S
authors.lastname: Paessler
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000956:Antigens, Viral / Q000302:isolation & purification; D000998:Antiviral Agents / Q000627:therapeutic use; D001253:Astrocytes / Q000821:virology; D001927:Brain Diseases / Q000188:drug therapy / Q000473:pathology / Q000821:virology*; D002490:Central Nervous System / Q000821:virology; D003517:Cyclopentanes / Q000627:therapeutic use; D016207:Cytokines / Q000276:immunology; D005289:Ferrets / Q000821:virology*; D006146:Guanidines / Q000627:therapeutic use; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D008590:Meningoencephalitis / Q000178:diet therapy / Q000662:veterinary* / Q000821:virology; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000662:veterinary* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000146:Acids, Carbocyclic; D000956:Antigens, Viral; D000998:Antiviral Agents; D003517:Cyclopentanes; D016207:Cytokines; D006146:Guanidines; D009439:Neuraminidase; C414210:peramivir