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.
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.
Stasakova
Jana
J
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Ferko
Boris
B
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Kittel
Christian
C
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Sereinig
Sabine
S
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Romanova
Julia
J
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Katinger
Hermann
H
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
Egorov
Andrej
A
Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Muthgasse 18B, A-1190 Vienna, Austria.
D017209:Apoptosis / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis*; D017353:Gene Deletion; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; C085820:INS1 protein, influenza virus; D007375:Interleukin-1; D020382:Interleukin-18; D017361:Viral Nonstructural Proteins; D020170:Caspase 1