title: Integrated clinical, pathologic, virologic, and transcriptomic analysis of H5N1 influenza virus-induced viral pneumonia in the rhesus macaque.
abstract: Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease.
authors.affiliation: Division of Zoonosis, Department of Microbiology and Infectious Disease, Graduate School of Medicine, Kobe University, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Gao
authors.forename: Cristian
authors.initials: C
authors.lastname: Cilloniz
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujie
authors.forename: Guohua
authors.initials: G
authors.lastname: Deng
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Zhu
authors.forename: Shufang
authors.initials: S
authors.lastname: Fan
authors.forename: Akiko
authors.initials: A
authors.lastname: Makino
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Muramoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Eisfeld
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Hualan
authors.initials: H
authors.lastname: Chen
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D008168:Lung / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology*; D011024:Pneumonia, Viral / Q000473:pathology* / Q000821:virology*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D059467:Transcriptome