20980503
not annotated - annotated - LINNAEUS only
Adenovirus membrane penetration activates the NLRP3 inflammasome.
Adenovirus type 5 (Ad5) infection of macrophages results in rapid secretion of interleukin-1Beta (IL-1Beta) and is dependent on the inflammasome components NLRP3 and ASC and the catalytic activity of caspase-1. Using lentivirus-expressed short hairpin RNA (shRNA) and competitive inhibitors, we show that Ad-induced IL-1Beta release is dependent upon Toll-like receptor 9 (TLR9) sensing of the Ad5 double-stranded DNA (dsDNA) genome in human cell lines and primary monocyte-derived macrophages but not in mouse macrophages. Additionally, a temperature-sensitive mutant of Ad5 unable to penetrate endosomal membranes, ts1, is unable to induce IL-1Beta release in TLR2-primed THP-1 cells, suggesting that penetration of endosomal membranes is required for IL-1Beta release. Disruption of lysosomal membranes and the release of cathepsin B into the cytoplasm are required for Ad-induced NLRP3 activation. Ad5 cell entry also induces reactive oxygen species (ROS) production, and inhibitors of ROS prevent Ad-induced IL-1Beta release. Ad5 activation of NLRP3 also induces necrotic cell death, resulting in the release of the proinflammatory molecule HMGB1. This work further defines the mechanisms of virally induced inflammasome activation.
Ann file
T1 Species 0 10 Adenovirus
N1 Reference T1 Taxonomy:10535
T2 Species 67 84 Adenovirus type 5
N2 Reference T2 Taxonomy:129951
T3 Species 86 89 Ad5
N3 Reference T3 Taxonomy:129951
T4 Species 461 464 Ad5
N4 Reference T4 Taxonomy:129951
T5 Species 503 508 human
N5 Reference T5 Taxonomy:9606
T6 Species 572 577 mouse
N6 Reference T6 Taxonomy:10090
T7 Species 639 642 Ad5
N7 Reference T7 Taxonomy:129951
T8 Species 940 942 Ad
N8 Reference T8 Taxonomy:10535
T9 Species 969 972 Ad5
N9 Reference T9 Taxonomy:129951
T10 Species 1069 1071 Ad
N10 Reference T10 Taxonomy:10535
T11 Species 1098 1101 Ad5
N11 Reference T11 Taxonomy:129951