tetano
Editor, Senior Moderator
Sci. Signal., 21 February 2012
Vol. 5, Issue 212, p. ra16
[DOI: 10.1126/scisignal.2001931]
RESEARCH ARTICLES
Inhibition of Autophagy Ameliorates Acute Lung Injury Caused by Avian Influenza A H5N1 Infection
Yang Sun1*, Chenggang Li1*, Yuelong Shu2*, Xiangwu Ju1, Zhen Zou1, Hongliang Wang1, Shuan Rao1, Feng Guo1, Haolin Liu1, Wenlong Nan3, Yan Zhao1, Yiwu Yan1, Jun Tang1, Chen Zhao1, Peng Yang1, Kangtai Liu1, Shunxin Wang1, Huijun Lu3, Xiao Li3, Lei Tan3, Rongbao Gao2, Jingdong Song2, Xiang Gao4, Xinlun Tian5, Yingzhi Qin5, Kai-Feng Xu5, Dangsheng Li6, Ningyi Jin3{dagger}, and Chengyu Jiang1{dagger}
1 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.
2 State Key Laboratory for Molecular Virology and Genetic Engineering, National Institute for Viral Disease Control and Prevention, China CDC, Changbai 155, Changping District, Beijing 102206, China.
3 Genetic Engineering Laboratory, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130062, China.
4 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, 22 Hankou Road, Nanjing 210093, China.
5 Peking Union Medical College Hospital, No.1 Shuaifuyuan, Beijing 100005, China.
6 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
* These authors contributed equally to this work.
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.
{dagger} To whom correspondence should be addressed. E-mail: jiang@pumc.edu.cn (C.J.); ningyij@yahoo.com (N.J.)
Citation: Y. Sun, C. Li, Y. Shu, X. Ju, Z. Zou, H. Wang, S. Rao, F. Guo, H. Liu, W. Nan, Y. Zhao, Y. Yan, J. Tang, C. Zhao, P. Yang, K. Liu, S. Wang, H. Lu, X. Li, L. Tan, R. Gao, J. Song, X. Gao, X. Tian, Y. Qin, K.-F. Xu, D. Li, N. Jin, C. Jiang, Inhibition of Autophagy Ameliorates Acute Lung Injury Caused by Avian Influenza A H5N1 Infection. Sci. Signal. 5, ra16 (2012).
http://stke.sciencemag.org/cgi/content/abstract/5/212/ra16?rss=1
Vol. 5, Issue 212, p. ra16
[DOI: 10.1126/scisignal.2001931]
RESEARCH ARTICLES
Inhibition of Autophagy Ameliorates Acute Lung Injury Caused by Avian Influenza A H5N1 Infection
Yang Sun1*, Chenggang Li1*, Yuelong Shu2*, Xiangwu Ju1, Zhen Zou1, Hongliang Wang1, Shuan Rao1, Feng Guo1, Haolin Liu1, Wenlong Nan3, Yan Zhao1, Yiwu Yan1, Jun Tang1, Chen Zhao1, Peng Yang1, Kangtai Liu1, Shunxin Wang1, Huijun Lu3, Xiao Li3, Lei Tan3, Rongbao Gao2, Jingdong Song2, Xiang Gao4, Xinlun Tian5, Yingzhi Qin5, Kai-Feng Xu5, Dangsheng Li6, Ningyi Jin3{dagger}, and Chengyu Jiang1{dagger}
1 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.
2 State Key Laboratory for Molecular Virology and Genetic Engineering, National Institute for Viral Disease Control and Prevention, China CDC, Changbai 155, Changping District, Beijing 102206, China.
3 Genetic Engineering Laboratory, Institute of Military Veterinary, Academy of Military Medical Sciences, Changchun 130062, China.
4 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, 22 Hankou Road, Nanjing 210093, China.
5 Peking Union Medical College Hospital, No.1 Shuaifuyuan, Beijing 100005, China.
6 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
* These authors contributed equally to this work.
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.
{dagger} To whom correspondence should be addressed. E-mail: jiang@pumc.edu.cn (C.J.); ningyij@yahoo.com (N.J.)
Citation: Y. Sun, C. Li, Y. Shu, X. Ju, Z. Zou, H. Wang, S. Rao, F. Guo, H. Liu, W. Nan, Y. Zhao, Y. Yan, J. Tang, C. Zhao, P. Yang, K. Liu, S. Wang, H. Lu, X. Li, L. Tan, R. Gao, J. Song, X. Gao, X. Tian, Y. Qin, K.-F. Xu, D. Li, N. Jin, C. Jiang, Inhibition of Autophagy Ameliorates Acute Lung Injury Caused by Avian Influenza A H5N1 Infection. Sci. Signal. 5, ra16 (2012).
http://stke.sciencemag.org/cgi/content/abstract/5/212/ra16?rss=1