title: Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection.
abstract: The threat of a new influenza pandemic has existed since 1997, when the highly pathogenic H5N1 strain of avian influenza A virus infected humans in Hong Kong and spread across Asia, where it continued to infect poultry and people. The human mortality rate of H5N1 infection is about 60%, whereas that of seasonal H1N1 infection is less than 0.1%. The high mortality rate associated with H5N1 infection is predominantly a result of respiratory failure caused by acute lung injury; however, how viral infection contributes to this disease pathology is unclear. Here, we used electron microscopy to show the accumulation of autophagosomes in H5N1-infected lungs from a human cadaver and mice, as well as in infected A549 human epithelial lung cells. We also showed that H5N1, but not seasonal H1N1, induced autophagic cell death in alveolar epithelial cells through a pathway involving the kinase Akt, the tumor suppressor protein TSC2, and the mammalian target of rapamycin. Additionally, we suggest that the hemagglutinin protein of H5N1 may be responsible for stimulating autophagy. When applied prophylactically, reagents that blocked virus-induced autophagic signaling substantially increased the survival rate of mice and substantially ameliorated the acute lung injury and mortality caused by H5N1 infection. We conclude that the autophagic cell death of alveolar epithelial cells likely plays a crucial role in the high mortality rate of H5N1 infection, and we suggest that autophagy-blocking agents might be useful as prophylactics and therapeutics against infection of humans by the H5N1 virus.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Tsinghua University, Beijing 100005, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Shu
authors.forename: Xiangwu
authors.initials: X
authors.lastname: Ju
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zou
authors.forename: Hongliang
authors.initials: H
authors.lastname: Wang
authors.forename: Shuan
authors.initials: S
authors.lastname: Rao
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Haolin
authors.initials: H
authors.lastname: Liu
authors.forename: Wenlong
authors.initials: W
authors.lastname: Nan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yiwu
authors.initials: Y
authors.lastname: Yan
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Kangtai
authors.initials: K
authors.lastname: Liu
authors.forename: Shunxin
authors.initials: S
authors.lastname: Wang
authors.forename: Huijun
authors.initials: H
authors.lastname: Lu
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Tan
authors.forename: Rongbao
authors.initials: R
authors.lastname: Gao
authors.forename: Jingdong
authors.initials: J
authors.lastname: Song
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Xinlun
authors.initials: X
authors.lastname: Tian
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Qin
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.forename: Ningyi
authors.initials: N
authors.lastname: Jin
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology; D055785:Gene Knockdown Techniques; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D007251:Influenza, Human / Q000473:pathology*; D008168:Lung / Q000648:ultrastructure* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010588:Phagosomes / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D017931:DNA Primers; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008869:Microtubule-Associated Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases