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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 1 and 18

Jana Stasakova

Boris Ferko

Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria

Correspondence
Andrej Egorov
a.egorov{at}iam.boku.ac.at

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-1) 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 IL1 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 IL1 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-IL1-, pro-IL18- and caspase-1-dependent apoptosis in infected primary human macrophages.

These authors contributed equally to this work.

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