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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Immunol
2017 ; 198
(4
): 1616-1626
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gab.com Text
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English Wikipedia
Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress
Syndrome in Aerosolized H5N1 Influenza Infection of Macaques
#MMPMID28062701
Wonderlich ER
; Swan ZD
; Bissel SJ
; Hartman AL
; Carney JP
; O'Malley KJ
; Obadan AO
; Santos J
; Walker R
; Sturgeon TJ
; Frye LJ Jr
; Maiello P
; Scanga CA
; Bowling JD
; Bouwer AL
; Duangkhae PA
; Wiley CA
; Flynn JL
; Wang J
; Cole KS
; Perez DR
; Reed DS
; Barratt-Boyes SM
J Immunol
2017[Feb]; 198
(4
): 1616-1626
PMID28062701
show ga
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-? 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.