title: Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus.
abstract: The mechanisms responsible for the virulence of the highly pathogenic avian influenza (HPAI) and of the 1918 pandemic influenza virus in humans remain poorly understood. To identify crucial components of the early host response during these infections by using both conventional and functional genomics tools, we studied 34 cynomolgus macaques (Macaca fascicularis) to compare a 2004 human H5N1 Vietnam isolate with 2 reassortant viruses possessing the 1918 hemagglutinin (HA) and neuraminidase (NA) surface proteins, known conveyors of virulence. One of the reassortants also contained the 1918 nonstructural (NS1) protein, an inhibitor of the host interferon response. Among these viruses, HPAI H5N1 was the most virulent. Within 24 h, the H5N1 virus produced severe bronchiolar and alveolar lesions. Notably, the H5N1 virus targeted type II pneumocytes throughout the 7-day infection, and induced the most dramatic and sustained expression of type I interferons and inflammatory and innate immune genes, as measured by genomic and protein assays. The H5N1 infection also resulted in prolonged margination of circulating T lymphocytes and notable apoptosis of activated dendritic cells in the lungs and draining lymph nodes early during infection. While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.
authors.affiliation: Washington National Primate Research Center, Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA. carole.baskin@asu.edu
authors.forename: Carole R
authors.initials: CR
authors.lastname: Baskin
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sabourin
authors.forename: James P
authors.initials: JP
authors.lastname: Long
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Airn-E
authors.initials: AE
authors.lastname: Tolnay
authors.forename: Randy
authors.initials: R
authors.lastname: Albrecht
authors.forename: John A
authors.initials: JA
authors.lastname: Pyles
authors.forename: Pam H
authors.initials: PH
authors.lastname: Olson
authors.forename: Lauri D
authors.initials: LD
authors.lastname: Aicher
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Rosenzweig
authors.forename: Kaja
authors.initials: K
authors.lastname: Murali-Krishna
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
authors.forename: Mark S
authors.initials: MS
authors.lastname: Kotur
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fornek
authors.forename: Sean
authors.initials: S
authors.lastname: Proll
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.forename: Carol L
authors.initials: CL
authors.lastname: Sabourin
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000472:pathogenicity; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D008171:Lung Diseases / Q000473:pathology / Q000821:virology; D008198:Lymph Nodes / Q000276:immunology; D008251:Macaca; D008297:Male; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D018523:Tropism; D014779:Virus Replication