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Glycosylation deletion of hemagglutinin head in the H5 subtype avian influenza virus enhances its virulence in mammals by inducing endoplasmic reticulum stress
Author(s) -
Yin Yuncong,
Yu Shengqing,
Sun Yingjie,
Qin Tao,
Chen Sujuan,
Ding Chan,
Peng Daxin,
Liu Xiufan
Publication year - 2020
Publication title -
transboundary and emerging diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.392
H-Index - 63
eISSN - 1865-1682
pISSN - 1865-1674
DOI - 10.1111/tbed.13481
Subject(s) - glycosylation , endoplasmic reticulum , biology , hemagglutinin (influenza) , virulence , phosphorylation , virus , unfolded protein response , virology , influenza a virus , xbp1 , microbiology and biotechnology , gene , biochemistry , rna splicing , rna
Hemagglutinin (HA) glycosylation of avian influenza virus (AIV) effects differently depending on the variation of glycosylation position and numbers. The natural mutation on the glycosylation sites of the AIV HA head occurs frequently. Our previous study shows that deletion of 158 or 169 glycosylation site on the HA head of the H5 subtype AIV strain rS‐144−/158+/169+ increases the viral virulence in mammals; however, the mechanism remains unknown. In this study, several AIVs with different deletions at HA head glycosylation sites 144, 158 or 169 were tested for their biological characteristics to clarify the possible mechanism. We found that rS‐144−/158−/169+ and rS‐144−/158+/169− viruses induced higher levels of inflammatory cytokines than rS‐144−/158+/169+ did in the infected cells, but the TCID 50 , EID 50 and MDT of the viruses showed no difference. Moreover, we found that rS‐144−/158−/169+ and rS‐144−/158+/169− viruses induced higher levels of endoplasmic reticulum (ER) stress in the cells. Inhibition of inositol‐requiring enzyme 1α (IRE1α) phosphorylation reduced the inflammation induced by AIV infection. Furthermore, we found that rS‐144−/158−/169+ virus activated the c‐Jun N‐terminal kinase (JNK), X‐box binding protein 1 (XBP1), and nuclear factor‐κB pathways by activating IRE1α phosphorylation under ER stress, whereas the rS‐144−/158+/169− virus activated only the JNK pathway by altering IRE1α phosphorylation. In vivo analysis of Kira6 intervention further confirmed that ER stress played a key role in higher virulence for HA head 158 or 169 site de‐glycosylation AIV. Our findings reveal that deletion of additional HA head glycosylation sites 158 or 169 enhanced the AIV virulence via activating of strong ER stress and inflammation.