title: Pandemic swine-origin H1N1 influenza A virus isolates show heterogeneous virulence in macaques.
abstract: The first influenza pandemic of the new millennium was caused by a newly emerged swine-origin influenza virus (SOIV) (H1N1). This new virus is characterized by a previously unknown constellation of gene segments derived from North American and Eurasian swine lineages and the absence of common markers predictive of human adaptation. Overall, human infections appeared to be mild, but an alarming number of young individuals presented with symptoms atypical for seasonal influenza. The new SOIV also showed a sustained human-to-human transmissibility and higher reproduction ratio than common seasonal viruses, altogether indicating a higher pathogenic potential for this newly emerged virus. To study the virulence of the SOIV, we used a recently established cynomolgus macaque model and compared parameters of clinical disease, virology, host responses, and pathology/histopathology with a current seasonal H1N1 virus. We here show that infection of macaques with two genetically similar but clinically distinct SOIV isolates from the early stage of the pandemic (A/Mexico/4108/2009 and A/Mexico/InDRE4487/2009) resulted in upper and lower respiratory tract infections and clinical disease ranging from mild to severe pneumonia that was clearly advanced over the mild infection caused by A/Kawasaki/UTK-4/2009, a current seasonal strain. Unexpectedly, we observed heterogeneity among the two SOIV isolates in virus replication, host transcriptional and cytokine responses, and disease progression, demonstrating a higher pathogenic potential for A/Mexico/InDRE4487/2009. Differences in virulence may explain more severe disease, as was seen with certain individuals infected with the emerged pandemic influenza virus. Thus, the nonhuman primate model closely mimics influenza in humans.
authors.affiliation: Laboratory of Virology, Hamilton, Montana, USA.
authors.forename: David
authors.initials: D
authors.lastname: Safronetz
authors.forename: Barry
authors.initials: B
authors.lastname: Rockx
authors.forename: Friederike
authors.initials: F
authors.lastname: Feldmann
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Belisle
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.forename: Douglas
authors.initials: D
authors.lastname: Brining
authors.forename: Don
authors.initials: D
authors.lastname: Gardner
authors.forename: Sean C
authors.initials: SC
authors.lastname: Proll
authors.forename: Andrea
authors.initials: A
authors.lastname: Marzi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Lacasse
authors.forename: Lisa
authors.initials: L
authors.lastname: Kercher
authors.forename: Anthony
authors.initials: A
authors.lastname: York
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.forename: Dan
authors.initials: D
authors.lastname: Long
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rosenke
authors.forename: W Lesley
authors.initials: WL
authors.lastname: Shupert
authors.forename: Celia Alpuche
authors.initials: CA
authors.lastname: Aranda
authors.forename: John S
authors.initials: JS
authors.lastname: Mattoon
authors.forename: Darwyn
authors.initials: D
authors.lastname: Kobasa
authors.forename: Gary
authors.initials: G
authors.lastname: Kobinger
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Richt
authors.forename: Michael
authors.initials: M
authors.lastname: Parnell
authors.forename: Hideki
authors.initials: H
authors.lastname: Ebihara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
mesh_terms: D000818:Animals; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000302:isolation & purification* / Q000472:pathogenicity*; D007251:Influenza, Human / Q000821:virology; D008251:Macaca; D008297:Male; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology*; D011024:Pneumonia, Viral / Q000473:pathology / Q000821:virology; D018419:Primate Diseases / Q000473:pathology* / Q000821:virology*; D012141:Respiratory Tract Infections / Q000473:pathology / Q000821:virology; D012720:Severity of Illness Index; D014774:Virulence
chemical_list: D016207:Cytokines