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J Immunol. 2017 Jan 6. pii: 1601770. doi: 10.4049/jimmunol.1601770. [Epub ahead of print]
Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques.
Wonderlich ER1,2, Swan ZD1,2, Bissel SJ3, Hartman AL1,2, Carney JP4, O'Malley KJ1,5, Obadan AO6, Santos J6, Walker R7, Sturgeon TJ1, Frye LJ Jr8, Maiello P8, Scanga CA8, Bowling JD1,2, Bouwer AL1,2, Duangkhae PA1,2, Wiley CA3, Flynn JL8, Wang J9, Cole KS1,5, Perez DR6, Reed DS1,5, Barratt-Boyes SM10,2,5.
Author information
Abstract
Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.
Copyright ? 2017 by The American Association of Immunologists, Inc.
PMID: 28062701 DOI: 10.4049/jimmunol.1601770
[PubMed - as supplied by publisher]
Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques.
Wonderlich ER1,2, Swan ZD1,2, Bissel SJ3, Hartman AL1,2, Carney JP4, O'Malley KJ1,5, Obadan AO6, Santos J6, Walker R7, Sturgeon TJ1, Frye LJ Jr8, Maiello P8, Scanga CA8, Bowling JD1,2, Bouwer AL1,2, Duangkhae PA1,2, Wiley CA3, Flynn JL8, Wang J9, Cole KS1,5, Perez DR6, Reed DS1,5, Barratt-Boyes SM10,2,5.
Author information
Abstract
Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.
Copyright ? 2017 by The American Association of Immunologists, Inc.
PMID: 28062701 DOI: 10.4049/jimmunol.1601770
[PubMed - as supplied by publisher]