Targeting Inflammasome Activation in Viral Infection: A Therapeutic Solution?

Abstract

Inflammasome activation is exclusively involved in sensing activation of innate immunity and inflammatory response during viral infection. Accumulating evidence suggests that the manipulation of inflammasome assembly or its interaction with viral proteins are critical factors in viral pathogenesis. Results from pilot clinical trials show encouraging results of NLRP3 inflammasome suppression in reducing mortality and morbidity in SARS-CoV-2-infected patients. In this article, we summarize the up-to-date understanding of inflammasomes, including NLRP3, AIM2, NLRP1, NLRP6, and NLRC4 in various viral infections, with particular focus on RNA viruses such as SARS-CoV-2, HIV, IAV, and Zika virus and DNA viruses such as herpes simplex virus 1. We also discuss the current achievement of the mechanisms involved in viral infection-induced inflammatory response, host defense, and possible therapeutic solutions.

Keywords: host defense; inflammasome; inflammatory response; innate immunity; therapy; viral infection.

Figure 1

Comparison of different inflammasomes. The PYD domain and the CARD domain of ASC serve as anchor points for the assembly of inflammasomes. However, NLRC4 itself carries the CARD domain, so ASC is not required to form the NLRC4 inflammasome. The figure was created in BioRender.

Figure 2

Compositions of different inflammasomes. Most of the identified inflammasomes are composed of NLR proteins, with the exception of NLR4, which recruits ASC by interacting with the PYD domain. The PYD and CARD domains of ASC serve as anchor points for subsequent recruitment of procaspase 1 to complete inflammasome assembly. NLRC4 itself carries the CARD domain, so it interacts directly with procaspase 1 and ASC is not required to form the NLRC4 inflammasome. The figure was created in BioRender.

Figure 3

SARS-CoV-2 activates the NLRP3 inflammasome through multiple pathways. SARS-CoV-2 infects macrophages through the Fcγ receptor. Viral proteins, such as S protein and NSP2, also stimulate NLRP3 transcription dependent on NF-κB signaling. N protein of SARS-CoV-2 directly interacts with NLRP3 to induce inflammasome formation and subsequent inflammatory response. dsDNA released from infected epithelial cells and mtDNA released from damaged mitochondria can also activate the inflammasome. The figure was created in BioRender.