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iTRAQ-based quantitative proteomics reveals important host factors involved in the high pathogenicity of the H5N1 avian influenza virus in mice

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Abstract

We previously reported a pair of H5N1 avian influenza viruses which are genetically similar but differ greatly in their virulence in mice. A/Chicken/Jiangsu/k0402/2010 (CK10) is highly lethal to mice, whereas A/Goose/Jiangsu/k0403/2010 (GS10) is avirulent. In this study, to investigate the host factors that account for their virulence discrepancy, we compared the pathology and host proteome of the CK10- or GS10-infected mouse lung. Moderate lung injury was observed from CK10-infected animals as early as the first day of infection, and the pathology steadily progressed at later time point. However, only mild lesions were observed in GS10-infected mouse lung at the late infection stage. Using the quantitative iTRAQ coupled LC–MS/MS method, we first found that more significantly differentially expressed (DE) proteins were stimulated by GS10 compared with CK10. However, bio-function analysis of the DE proteins suggested that CK10 induced much stronger inflammatory response-related functions than GS10. Canonical pathway analysis also demonstrated that CK10 highly activated the “Acute Phase Response Signaling,” which results in a wide range of biological activities in response to viral infection, including many inflammatory processes. Further in-depth analysis showed that CK10 exacerbated acute lung injury-associated responses, including inflammatory response, cell death, reactive oxygen species production and complement response. In addition, some of these identified proteins that associated with the lung injury were further confirmed to be regulated in vitro. Therefore, our findings suggest that the early increased lung injury-associated host response induced by CK10 may contribute to the lung pathology and the high virulence of this virus in mice.

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Abbreviations

SILAC:

Stable isotope labeling by amino acids in cell culture

iTRAQ:

Isobaric tags for relative and absolute quantitation

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

SCX:

Strong cation exchange

HPLC:

High-performance liquid chromatography

IPA:

Ingenuity Pathways Analysis

qRT-PCR:

Quantitative real-time RT-PCR

HCD:

Higher-energy collision-induced dissociation

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

LXR/RXR:

Liver X receptor/retinoid X receptor

FXR/RXR:

Farnesoid X receptor/retinoid X receptor

LPS:

Lipopolysaccharide

LTA:

Lymphotoxin alpha

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31502076), by the Jiangsu Provincial Natural Science Foundation of China (BK20150444), by the Special Financial Grant from the China Postdoctoral Science Foundation (2016T90515), by the National Key Research and Development Project of China (2016YFD0501601 and 2016YFD0500202), by the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (15KJB230006), by the National Key Technologies R&D Program of China (2015BAD12B01-3), by the earmarked fund for Modern Agro-industry Technology Research System (nycytx-41-G07) and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    1. Animal Infectious Disease Laboratory, School of Veterinary Medicine, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu Province, China

      Jiao Hu, Zhao Gao, Xiaoquan Wang, Min Gu, Yanyan Liang, Xiaowen Liu, Shunlin Hu, Huimou Liu, Wenbo Liu, Sujuan Chen, Daxin Peng & Xiufan Liu

    2. Jiangsu Key Laboratory of Zoonosis, Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, China

      Jiao Hu, Zhao Gao, Xiaoquan Wang, Min Gu, Yanyan Liang, Xiaowen Liu, Shunlin Hu, Huimou Liu, Wenbo Liu, Sujuan Chen, Daxin Peng & Xiufan Liu

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    Jiao Hu, Zhao Gao, Xiaoquan Wang, Min Gu, Yanyan Liang, Xiaowen Liu, Shunlin Hu, Huimou Liu, Wenbo Liu, Sujuan Chen, Daxin Peng and Xiufan Liu declare that they have no conflict of interests.

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    Figure S1

    Top one canonical pathway “Acute phase response signaling” induced by GS10. (TIFF 941 kb)

    Figure S2

    Top five canonical pathway “Complement system” triggered by CK10. (TIFF 816 kb)

    Figure S3

    Top four canonical pathway “Antigen presentation pathway” stimulated by CK10. (TIFF 1409 kb)

    Figure S4

    Network of virus–host interactions. Interactions among the viral proteins and the host factors identified here were visualized by using cytoscape (http://cytoscape.org/). This picture shows the protein–protein interactions of the DE proteins induced by GS10. (TIFF 1819 kb)

    Figure S5

    Network of virus–host interactions. Interactions among the viral proteins and the host factors identified here were visualized by using cytoscape (http://cytoscape.org/). This picture shows the direct protein–protein interactions of the DE proteins induced by CK10. (TIFF 297 kb)

    Figure S6

    Network of virus–host interactions. Interactions among the viral proteins and the host factors identified here were visualized by using cytoscape (http://cytoscape.org/). This picture shows the direct protein–protein interactions of the DE proteins induced by GS10. (TIFF 1973 kb)

    Supplementary material 7 (DOC 131 kb)

    Supplementary material 8 (DOC 258 kb)

    Supplementary material 9 (XLS 201 kb)

    Supplementary material 10 (XLS 184 kb)

    Supplementary material 11 (XLS 20 kb)

    Supplementary material 12 (XLS 34 kb)

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    Hu, J., Gao, Z., Wang, X. et al. iTRAQ-based quantitative proteomics reveals important host factors involved in the high pathogenicity of the H5N1 avian influenza virus in mice. Med Microbiol Immunol 206, 125–147 (2017). https://doi.org/10.1007/s00430-016-0489-3

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