Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18

• Published in: Journal of general virology Vol. 86; no. Pt 1; pp. 185 - 195
• Main Authors: Stasakova, Jana, Ferko, Boris, Kittel, Christian, Sereinig, Sabine, Romanova, Julia, Katinger, Hermann, Egorov, Andrej
• Format: Journal Article
• Language: English
• Published: England 01.01.2005
• Subjects: Apoptosis - physiology; Caspase 1 - metabolism; Cytokines - biosynthesis; Gene Deletion; Humans; Influenza A virus - genetics; Influenza A virus - physiology; Interleukin-1 - biosynthesis; Interleukin-18 - biosynthesis; Macrophages - enzymology; Macrophages - immunology; Macrophages - virology; Up-Regulation; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - physiology
• ISSN: 0022-1317
• DOI: 10.1099/vir.0.80422-0

Several NS1 mutant viruses of human influenza A/PR/8/34 (H1N1) virus were tested for their ability to induce pro-inflammatory cytokines in primary human macrophages. The findings revealed a pronounced difference in the virus-induced cytokine pattern, depending on the functionality of the NS1 protein-encoded domains. The PR8/NS1-125 mutant virus, which encodes the first 125 aa of the NS1 protein, thus lacking the C-terminal domains, induced significantly higher amounts of beta interferon, interleukin (IL) 6, tumour necrosis factor alpha and CCL3 (MIP-1alpha) when compared with the A/PR/8/34 wild-type virus. However, this mutant virus was as efficient as wild-type virus in the inhibition of IL1beta and IL18 release from infected macrophages. Another group of viral mutants either lacking or possessing non-functional RNA-binding and dimerization domains induced 10-50 times more biologically active IL1beta and five times more biologically active IL18 than the wild-type or PR8/NS1-125 viruses. The hallmark of infection with this group of mutant viruses was the induction of rapid apoptosis in infected macrophages, which correlated with the enhanced activity of caspase-1. These results indicated that the NS1 protein, through the function of its N-terminal domains, might control caspase-1 activation, thus repressing the maturation of pro-IL1beta-, pro-IL18- and caspase-1-dependent apoptosis in infected primary human macrophages.