Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques.
Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques.
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DOI：
10.4049/jimmunol.1601770
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发表时间：
2017-02-15
期刊：
影响因子：
--
通讯作者：
Barratt-Boyes SM
中科院分区：
文献类型：
--
作者：
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
人类感染高致病性禽流感A（H5 N1）病毒通常是致命的，但疾病的机制仍然不明确。H5 N1感染与促炎细胞因子的大量产生有关，但这种细胞因子风暴是否是致命的主要原因，或者是病毒广泛复制本身驱动疾病的结果仍然存在争议。在非人灵长类动物中常规的H5 N1流感病毒液体悬液的气管内接种可能导致上呼吸道内病毒的有效清除，并且很少产生严重的疾病。我们推断病毒的小颗粒气溶胶会穿透下呼吸道并覆盖靶细胞所在的肺泡。我们表明，食蟹猴吸入雾化H5 N1流感病毒导致暴发性肺炎，迅速发展为急性呼吸窘迫综合征，致命的结果让人联想到人类疾病。分子影像学显示，肺部炎症严重，同时远端气道中促炎蛋白和干扰素-α大量增加。雾化的H5 N1暴露使肺泡巨噬细胞大量减少，肺泡巨噬细胞被广泛感染并引起间质巨噬细胞和中性粒细胞的显著流入。肺泡上皮细胞的广泛感染引起细胞凋亡和白蛋白渗漏到气道中，反映了上皮屏障功能的丧失。这些数据确定吸入雾化病毒是致命性人类感染的一个关键接触源，并揭示病毒在肺泡中的直接作用介导H5 N1疾病。这种新的非人灵长类动物模型将推进疫苗和治疗方法，以预防和治疗由高致病性禽流感病毒引起的人类疾病。
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 interferon-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.
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影响因子：
11.8
作者：
Arriola CS;Nelson DI;Deliberto TJ;Blanton L;Kniss K;Levine MZ;Trock SC;Finelli L;Jhung MA;H5 Investigation Group
通讯作者：
H5 Investigation Group
影响因子：
0.7
作者：
Brown KN;Barratt-Boyes SM
通讯作者：
Barratt-Boyes SM
DOI：
10.4049/jimmunol.1302269
发表时间：
2014-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cai Y;Sugimoto C;Arainga M;Alvarez X;Didier ES;Kuroda MJ
通讯作者：
Kuroda MJ
DOI：
10.1016/j.vascn.2003.07.001
发表时间：
2004-01-01
影响因子：
1.9
作者：
Hartings, Justin M.;Roy, Chad J.
通讯作者：
Roy, Chad J.
影响因子：
158.5
作者：
de Jong, MD;Van Cam, B;Farrar, J
通讯作者：
Farrar, J