title: Histopathological evaluation of the diversity of cells susceptible to H5N1 virulent avian influenza virus.
abstract: Patients infected with highly pathogenic avian influenza A H5N1 viruses (H5N1 HPAIV) show diffuse alveolar damage. However, the temporal progression of tissue damage and repair after viral infection remains poorly defined. Therefore, we assessed the sequential histopathological characteristics of mouse lung after intranasal infection with H5N1 HPAIV or H1N1 2009 pandemic influenza virus (H1N1 pdm). We determined the amount and localization of virus in the lung through IHC staining and in situ hybridization. IHC used antibodies raised against the virus protein and antibodies specific for macrophages, type II pneumocytes, or proliferating cell nuclear antigen. In situ hybridization used RNA probes against both viral RNA and mRNA encoding the nucleoprotein and the hemagglutinin protein. H5N1 HPAIV infection and replication were observed in multiple lung cell types and might result in rapid progression of lung injury. Both type II pneumocytes and macrophages proliferated after H5N1 HPAIV infection. However, the abundant macrophages failed to block the viral attack, and proliferation of type II pneumocytes failed to restore the damaged alveoli. In contrast, mice infected with H1N1 pdm exhibited modest proliferation of type II pneumocytes and macrophages and slight alveolar damage. These results suggest that the virulence of H5N1 HPAIV results from the wide range of cell tropism of the virus, excessive virus replication, and rapid development of diffuse alveolar damage.
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Haru
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yasui
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Munekata
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Takagi-Kamiya
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Munakata
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shibasaki
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
authors.affiliation: Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: kohara-mc@igakuken.or.jp.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
mesh_terms: D056809:Alveolar Epithelial Cells / Q000473:pathology / Q000821:virology*; D000818:Animals; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053118:Influenza A Virus, H1N1 Subtype; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity / Q000502:physiology*; D008264:Macrophages / Q000473:pathology / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology; D011024:Pneumonia, Viral / Q000473:pathology* / Q000821:virology*; D014779:Virus Replication / Q000502:physiology