Detection of viruses by inflammasomes

Abstract

The innate immune system has evolved mechanisms to keep the viral infection under control and repair damaged tissues. Several pathways can identify the presence of pathogenic components, such as viral nucleic acids and viral proteins. Also, the innate immune system can detect cellular and tissue perturbations caused by infections. Inflammasomes are cellular pieces of machinery that can detect a pathogen's presence and its possible impact on cellular integrity. Thereby several inflammasomes, including the NLRP3 inflammasome and the AIM2 inflammasome, contribute to antiviral innate immunity. Inflammation driven by inflammasomes promotes immune defenses and initiate repair mechanisms. However, its overactivation may trigger acute inflammatory responses that may harm the host. This pathologic activation could contribute to the hyperinflammatory response observed in patients infected with viruses, including influenza, SARS, and possibly SARS-CoV2.

Figure 1

Generic NLRP3 inflammasome activation. Upon infection, a priming signal is generated (a). Pathways such as TLRs are engaged and induce NFκB and Type I Interferon. These transcriptional programs can upregulate gene transcription of inflammasome components, including NLRP3, Caspase-1, and ASC, as well as inflammasome substrates proIL-1β, proIL-18, and GSDMD. Then, viral products, as well as perturbation of cellular integrity, may initiate an activation program (b), leading to the oligomerization and assembly of the active inflammasome complex. Inflammasome proteolytic activity mediated by the caspase-1 will cleave its substrates. Cleaved GSDMD forms membrane pores. These pores permeabilize the plasma membrane facilitating the passive release of cleaved cytokines IL-1β and IL-18. GSDMD pores can also destabilize the membrane to cause cell death, triggering the leakage of cellular content by a process termed pyroptosis. IL-1β, IL-18, and other inflammatory mediators released upon pyroptosis will contribute to immune responses and initiate an inflammatory cascade.

Figure 2

Viroporins mediated inflammasome activation. Viral viroporins trigger perturbations in cellular integrity and ionic balances leading to NLRP3 inflammasome activation. By forming pores in intracellular compartments such as the TGN, and the plasma membrane, viroporins permeabilize membranes leading to the influx of Ca²⁺ and efflux of K+. These changes are detected by NLRP3 as a signal 2, leading to inflammasome assembly. The cleavage of GSDMD by the inflammasome leads to the formation of GSDMD pores that mimic the effects of viroporins, thereby amplifying the ionic imbalance and inflammasome activation. Edited by Allan J Zajac and Annette Oxenius For complete overview of the section, please refer the article collection – Viral Immunology (2021) and https://www.sciencedirect.com/topics/medicine-and-dentistry/viral-immunology Available online 4th November 2020