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. 2012 Feb 21;5(212):ra16.
doi: 10.1126/scisignal.2001931.

Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection

Yang Sun  1 , Chenggang Li, Yuelong Shu, Xiangwu Ju, Zhen Zou, Hongliang Wang, Shuan Rao, Feng Guo, Haolin Liu, Wenlong Nan, Yan Zhao, Yiwu Yan, Jun Tang, Chen Zhao, Peng Yang, Kangtai Liu, Shunxin Wang, Huijun Lu, Xiao Li, Lei Tan, Rongbao Gao, Jingdong Song, Xiang Gao, Xinlun Tian, Yingzhi Qin, Kai-Feng Xu, Dangsheng Li, Ningyi Jin, Chengyu Jiang
Affiliations

Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection

Yang Sun et al. Sci Signal. .

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.

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