Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?
Abstract
Background In 1997, the first documented instance of human respiratory disease and death associated with a purely avian H5N1 influenza virus resulted in an overall case-fatality rate of 33%. The biological basis for the severity of human H5N1 disease has remained unclear. We tested the hypothesis that virus-induced cytokine dysregulation has a role.Methods We used cDNA arrays and quantitative RT-PCR to compare the profile of cytokine gene expression induced by viruses A/HK/486/97 and A/HK/483/97 (both H5N1/97) with that of human H3N2 and H1N1 viruses in human primary monocyte-derived macrophages in vitro. Secretion of tumour necrosis factor alpha (TNF alpha) from macrophages infected with the viruses was compared by ELISA. By use of naturally occurring viral reassortants and recombinant viruses generated by reverse genetic techniques, we investigated the viral genes associated with the TNF-alpha response.Findings The H5N1/97 viruses induced much higher gene transcription of proinflammatory cytokines than did H3N2 or H1N1 viruses, particularly TNF alpha and interferon beta. The concentration of TNF-alpha protein in culture supernatants of macrophages infected with these viruses was similar to that induced by stimulation with Escherichia coli lipopolysaccharide. The non-structural (NS) gene-segment of H5N1/97 viruses contributed to the increase in TNF alpha induced by the virus.Interpretation The H5N1/97 viruses are potent inducers of proinflammatory cytokines in macrophages, the most notable being TNF alpha. This characteristic may contribute to the unusual severity of human H5N1 disease.
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TNF is highly expressed across infection models, including primary human respiratory epithelial cells and human monocyte-derived macrophages, compared with seasonal H1N1 and swine-origin H1N1 influenza virus infection.
“It is highly expressed across infection models, including primary human respiratory epithelial cells (24, 125) and human monocyte-derived macrophages (26, 59, 62), compared with during seasonal H1N1 influenza virus and swine-origin H1N1 influenza virus (SOIV) infection (111).”
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- Authors
- Cheung, C., Poon, L., Lau, A., Luk, W., Lau, Y., Shortridge, K., Gordon, S., Guan, Y., & Peiris, J.
- Affiliations
- Queen Mary Hospital (CN)
- University of Oxford (GB)
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 360
- Issue
- 9348
- Pages
- 1831-1837
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2122399224
- Cited by
- 889
- References
- 30
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 15 · 2023: 10 · 2022: 23 · 2021: 33 · 2020: 58 · 2019: 26 · 2018: 28 · 2017: 24 · 2016: 24 · 2015: 40 · 2014: 43 · 2013: 51 · 2012: 50
- FWCI
- 20.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- H5N1 influenza virus, inflammatory cytokines, macrophages, TNF-α, interferon-beta, cytokine gene expression, viral pathogenicity, disease severity, monocyte-derived macrophages
- MeSH terms
- Cells, Cultured, Gene Expression Regulation, Humans, Influenza, Human, Macrophages, RNA, Messenger, Severity of Illness Index, Tumor Necrosis Factor-alpha, Cytokines, Alphainfluenzavirus
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