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Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells

MCW Chan1, CY Cheung1, WH Chui2, SW Tsao3, JM Nicholls4, YO Chan1, RWY Chan1, HT Long5, LLM Poon1, Y Guan1 and JSM Peiris1*

Author Affiliations

1 Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region of China

2 Department of Cardiothoracic Surgery, Grantham Hospital, Wong Chuk Hang, Aberdeen, Hong Kong Special Administrative Region of China

3 Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of China

4 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region of China

5 National Institute of Hygiene and Epidemiology, Hanoi, Vietnam

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Respiratory Research 2005, 6:135  doi:10.1186/1465-9921-6-135

Published: 11 November 2005

Abstract

Background

Fatal human respiratory disease associated with influenza A subtype H5N1 has been documented in Hong Kong, and more recently in Vietnam, Thailand and Cambodia. We previously demonstrated that patients with H5N1 disease had unusually high serum levels of IP-10 (interferon-gamma-inducible protein-10). Furthermore, when compared with human influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97) (H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor necrosis factor-a) and chemokines (e.g. IP-10) from primary human macrophages in vitro, which suggests that cytokines dysregulation may play a role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the primary target cell for replication of influenza viruses, it is pertinent to investigate the cytokine induction profile of H5N1 viruses in these cells.

Methods

We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro.

Results

We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus.

Conclusion

The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease.

Keywords:
avian; chemokines; IP-10; pathogenesis