Journal
VIRUSES-BASEL
Volume 10, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/v10100567
Keywords
human cytomegalovirus (HCMV); pp65; inflammasome; interleukin-1 beta (IL-1 beta); caspase-8
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Funding
- Italian Ministry of Education, University and Research - MIUR [2015W729WH, 2015RMNSTA]
- Compagnia di San Paolo
- University of Turin
- European Commission under the Horizon2020 program [H2020 MSCA-ITN GA 675278 EDGE]
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Interleukin-1 beta (IL-1 beta) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1 beta into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1 beta production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1 beta compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1 beta. Furthermore, we show that enhanced IL-1 beta production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-kappa B. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1 beta activation pathway where caspase-8 promotes IL-1 beta maturation independently of caspase-1 beta. Altogether, our findings provide novel mechanistic insights into the interplay between HCMV and the inflammasome system and raise the possibility of targeting pp65 to treat HCMV infection.
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