Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression.
Despite vaccines and antiviral substances influenza still causes significant morbidity and mortality world wide. Better understanding of the molecular mechanisms of influenza virus replication, pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza. Influenza A virus, which replicates in epithelial cells and leukocytes, regulates host cell transcriptional and translational systems and activates, as well as downregulates apoptotic pathways. Influenza A virus infection results in the production of chemotactic (RANTES, MIP-1 alpha, MCP-1, MCP-3, and IP-10), pro-inflammatory (IL-1 beta, IL-6, IL-18, and TNF-alpha), and antiviral (IFN-alpha/beta) cytokines. Cytokine gene expression is associated with the activation of NF-kappa B, AP-1, STAT and IRF signal transducing molecules in influenza A virus-infected cells. In addition of upregulating cytokine gene expression, influenza A virus infection activates caspase-1 enzyme, which is involved in the proteolytic processing of proIL-1 beta and proIL-18 into their biologically active forms. Influenza A virus-induced IFN-alpha/beta is essential in host's antiviral defence by activating the expression of antiviral Mx, PKR and oligoadenylate synthetase genes. IFN-alpha/beta also prolongs T cell survival, upregulates IL-12 and IL-18 receptor gene expression and together with IL-18 stimulates NK and T cell IFN-gamma production and the development of Th1-type immune response.
Julkunen
I
I
Department of Virology, National Public Health Institute, Laboratory of Viral and Molecular Immunology, Mannerheimintie 166, FIN-00300 Helsinki, Finland. ilkka.julkunen@ktl.fi
Sareneva
T
T
Pirhonen
J
J
Ronni
T
T
Melén
K
K
Matikainen
S
S
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D016207:Cytokines; D014157:Transcription Factors; D020169:Caspases