Myxoma Virus Lacking the Pyrin-Like Protein M013 Is Sensed in Human Myeloid Cells by both NLRP3 and Multiple Toll-Like Receptors, Which Independently Activate the Inflammasome and NF-κB Innate Response Pathways

Abstract

The myxoma virus (MYXV)-encoded pyrin domain-containing protein M013 coregulates inflammatory responses mediated by both the inflammasome and the NF-κB pathways. Infection of human THP-1 monocytic cells with a MYXV construct deleted for the M013 gene (vMyxM013-KO), but not the parental MYXV, activates both the inflammasome and NF-κB pathways and induces a spectrum of proinflammatory cytokines and chemokines, like interleukin-1β (IL-1β), tumor necrosis factor (TNF), IL-6, and monocyte chemoattractant protein 1. Here, we report that vMyxM013-KO virus-mediated activation of inflammasomes and secretion of IL-1β are dependent on the adaptor protein ASC, caspase-1, and NLRP3 receptor. However, vMyxM013-KO virus-mediated activation of NF-κB signaling, which induces TNF secretion, was independent of ASC, caspase-1, and either the NLRP3 or AIM2 inflammasome receptors. We also report that early synthesis of pro-IL-1β in response to vMyxM013-KO infection is dependent upon the components of the inflammasome complex. Activation of the NLRP3 inflammasome and secretion of IL-1β was also dependent on the release of cathepsin B and production of reactive oxygen species (ROS). By using small interfering RNA screening, we further demonstrated that, among the RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs), only TLR2, TLR6, TLR7, and TLR9 contribute to the NF-κB-dependent secretion of TNF and the inflammasome-dependent secretion of IL-1β in response to vMyxM013-KO virus infection. Additionally, we demonstrate that early triggering of the mitogen-activated protein kinase pathway by vMyxM013-KO virus infection of THP-1 cells plays a critical common upstream role in the coordinate induction of both NF-κB and inflammasome pathways. We conclude that an additional cellular sensor(s)/receptor(s) in addition to the known RLRs/TLRs plays a role in the M013 knockout virus-induced activation of NF-κB pathway signaling, but the activation of inflammasomes entirely depends on sensing by the NLRP3 receptor in response to vMyxM013-KO infection of human myeloid cells.

Inflammasome Adaptor Protein Apoptosis-Associated Speck-Like Protein Containing CARD (ASC) Is Critical for the Immune Response and Survival in West Nile Virus Encephalitis

“…Several studies have recently revealed the in vivo role of ASC in different physiological and pathological events associated with inflammation (20). DNA viruses, including vaccinia virus, adenovirus, myxoma virus, and mouse cytomegalovirus (21)(22)(23), and RNA viruses, such as influenza A virus, Sendai virus, human respiratory syncytial virus, and encephalomyocarditis virus (EMCV), utilize the inflammasome assembly to induce IL-1␤ production (12,24,25). In another seminal study, Ichinohe et al reported that ASC inflammasomes play a central role in innate and adaptive immunity to influenza virus (26).…”

DDX19A Senses Viral RNA and Mediates NLRP3-Dependent Inflammasome Activation

“…It has been demonstrated that viral infections can induce the NLRP3 inflammasome activation (10,17,(58)(59)(60). We then investigated whether the NLRP3-ASC-caspase-1 complex is formed in response to HP-PRRSV infection.…”

HIV-1 Infection Induces Interleukin-1β Production via TLR8 Protein-dependent and NLRP3 Inflammasome Mechanisms in Human Monocytes

“…Several types of viruses, including influenza A virus, dengue virus, hepatitis C virus, adenovirus, varicella zoster virus, encephalomyocarditis virus, vesicular stomatitis virus, myxoma virus, and respiratory syncytial virus have been found to induce IL-1␤ through the NLRP3 inflammasome (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Interestingly, HIV-1 infection has been reported to induce NLRP3 mRNA expression in monocyte-derived dendritic cells (32), and an SNP at the 3Ј UTR of the NLRP3 gene is associated with susceptibility to HIV-1 infection (33).…”