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

J Gen Virol. 2005 Jan;86(Pt 1):185-195. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Cytokines
  • INS1 protein, influenza virus
  • Interleukin-1
  • Interleukin-18
  • Viral Nonstructural Proteins
  • Caspase 1