Journal
TRANSBOUNDARY AND EMERGING DISEASES
Volume 67, Issue 4, Pages 1492-1506Publisher
WILEY-HINDAWI
DOI: 10.1111/tbed.13481
Keywords
avian influenza virus; endoplasmic reticulum stress; glycosylation; hemagglutinin; Kira6
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Funding
- National Key RD Project [2016YFD0500202, 2018YFD0500100]
- National Natural Science Foundation of China [31872473, 31602057]
- Independent Innovation of Agricultural Sciences in Jiangsu Province [CX (18) 3018]
- Priority Academic Program Development of Jiangsu Higher Education
- Jiangsu Province Natural Science Foundation of China [BK20160456]
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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 TCID50, EID50 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 1 alpha (IRE1 alpha) 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-kappa B pathways by activating IRE1 alpha phosphorylation under ER stress, whereas the rS-144-/158+/169- virus activated only the JNK pathway by altering IRE1 alpha 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.
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