The hemagglutinin protein of influenza A/Vietnam/1203/2004 (H5N1) contributes to hyperinduction of proinflammatory cytokines in human epithelial cells

• Published in: Virology (New York, N.Y.) Vol. 406; no. 1; pp. 28 - 36
• Main Authors: Cheng, Xing, Xu, Qi, Song, Eyun, Yang, Chin-Fen, Kemble, George, Jin, Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2010
• Subjects: Cell Line; Cytokine; Cytokines - biosynthesis; Cytokines - genetics; Epithelial Cells - immunology; Epithelial Cells - virology; Gene Expression; H5N1 vaccine; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Infectious Disease; Inflammation Mediators - metabolism; Influenza A Virus, H5N1 Subtype - genetics; Influenza A Virus, H5N1 Subtype - immunology; Influenza Vaccines - genetics; Influenza Vaccines - immunology; Interferon Type I - biosynthesis; Interferon Type I - genetics; Live attenuated influenza A virus; Neuraminidase - genetics; Neuraminidase - immunology; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; H5N1 vaccine; Live attenuated influenza A virus; Cytokine
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2010.06.048

Abstract Live attenuated influenza A/Vietnam/1203/04 (H5N1) (VN04 cold adapted [ ca ]) and A/Hong Kong/213/03 (H5N1) (HK03 ca ) vaccine viruses were compared with the A/New Caledonia/20/99 (H1N1) (NC99 ca ) seasonal vaccine virus for induction of host gene expression in infected human epithelial cells. Levels of proinflammatory cytokines and interferon-related genes were significantly upregulated in VN04 ca virus-infected A549 cells compared to cells infected with the HK03 ca and NC99 ca viruses as examined by microarray analysis and confirmed by quantitative RT–PCR and ELISA assays. Further mapping studies demonstrated that the hemagglutinin (HA) protein of the VN04 ca virus contributed to the hyperinduction of cytokines. The inactivated viruses could also induce the production of the cytokines and chemokines, albeit at a much lower level than live viruses. Compared to HK03 ca virus, VN04 ca virus differs by 9 amino acids including an additional glycosylation site at residue 158N of the HA protein and a shortened stalk in the neuraminidase (NA) protein. Increased cytokine production by HK03 ca virus was only observed when HK03 ca virus acquired an additional glycosylation in the HA protein and when its NA protein was replaced by that of VN04. Thus, our data indicate that the HA protein and its interaction with the NA protein play a role in triggering cytokine responses. The full implications of cytokine induction in vaccine virus-induced immune responses remain to be explored.