Inflammasome activation by viral infection: mechanisms of activation and regulation

Abstract

Viral diseases are the most common problems threatening human health, livestock, and poultry industries worldwide. Viral infection is a complex and competitive dynamic biological process between a virus and a host/target cell. During viral infection, inflammasomes play important roles in the host and confer defense mechanisms against the virus. Inflammasomes are polymeric protein complexes and are considered important components of the innate immune system. These immune factors recognize the signals of cell damage or pathogenic microbial infection after activation by the canonical pathway or non-canonical pathway and transmit signals to the immune system to initiate the inflammatory responses. However, some viruses inhibit the activation of the inflammasomes in order to replicate and proliferate in the host. In recent years, the role of inflammasome activation and/or inhibition during viral infection has been increasingly recognized. Therefore, in this review, we describe the biological properties of the inflammasome associated with viral infection, discuss the potential mechanisms that activate and/or inhibit NLRP1, NLRP3, and AIM2 inflammasomes by different viruses, and summarize the reciprocal regulatory effects of viral infection on the NLRP3 inflammasome in order to explore the relationship between viral infection and inflammasomes. This review will pave the way for future studies on the activation mechanisms of inflammasomes and provide novel insights for the development of antiviral therapies.

Keywords: Inflammasome; NLRP; inflammatory response; regulation; virus infection.

Figure 1

Mechanisms and consequences of inflammasome activation (Martinon et al., 2002; Shi J. et al., 2015). Once the viral particles are captured by TLRs, the associated antiviral genes begin to be transcribed and translated. For the NLRP3 inflammasome, dsRNA viruses induce K⁺ efflux, Ca2⁺ mobilization, and/or ROS or dTGN production to activate the NLRP3 inflammasome. The hNLRP1 inflammasome can be activated by RNA, viral nucleic acid, viral pathogen enzymes, and viral structural proteins. The AIM2 inflammasome can be activated by DNA or viral nucleic acid. Activated inflammasomes recruit and activate pro-caspase-1 to cleave the GSDMD, pro-IL-1β, and pro-IL-18. The C-terminal domain of gasdermin D can induce pyroptosis, resulting in the release of large amounts of pro-inflammatory cytokines and causing acute or chronic inflammation.

Figure 2

Viruses act as inducers and have different effects on individual inflammasomes. For example, the NLRP1 inflammasome is activated by the Herpesviridae family virus, the Togaviridae family virus, and the Picornaviridae family virus; for the NLRP3 inflammasome, the invasion of the Paramyxairidae family virus, the Flaviviridae family virus, the Coronaviridae family virus, the Picornaviridae family virus, and the Herpesviridae family virus is the cause of activation, whereas the AIM2 inflammasome is activated by the Herpesviridae family virus, the Flaviridae family virus, and the Picornaviridae family virus. The activation of the inflammasome then triggers the pyroptosis.

Figure 3

Reciprocal regulation between viruses and the NLRP3 inflammasome. The M2 protein of the influenza A virus causes dTGN dispersion to activate NLRP3 inflammasome, while the NS1 C-terminus of the pandemic H1N1 2009 virus inhibits ASC ubiquitination and thus inhibits the NLRP3 inflammasome. The enterovirus 71 3D protein binds directly to the NACHT and LRR domains of NLRP3 to activate it. However, the EV71 viral proteases 3C and 2A cleave the NLRP3 protein at the Q225-G226 and G493-L494 junctions to inhibit the NLRP3 activation inflammasome. Zika virus non-structural protein 5 (NS5) binds directly to the NACHT and LRR domains of NLRP3 to facilitate the assembly of the NLRP3 inflammasome complex, but NS3 acts directly on NLRP3 to inhibit its activation. The 260–340 aa domain of the N protein of SARSV-CoV-2 binds to NLRP3 and the NSP6 binds to ATP6API by impairing lysosomal acidification to promote NLRP3 inflammasome activation, while the NSP1 and NSP13 of SARS-CoV-2 inhibit caspase-1 activity to interfere with NLRP3 activation.