Pyroptosis and Its Role in SARS-CoV-2 Infection

Abstract

The pore-forming inflammatory cell death pathway, pyroptosis, was first described in the early 1990s and its role in health and disease has been intensively studied since. The effector molecule GSDMD is cleaved by activated caspases, mainly Caspase 1 or 11 (Caspase 4/5 in humans), downstream of inflammasome formation. In this review, we describe the molecular events related to GSDMD-mediated pore formation. Furthermore, we summarize the so far elucidated ways of SARS-CoV-2 induced NLRP3 inflammasome formation leading to pyroptosis, which strongly contributes to COVID-19 pathology. We also explore the potential of NLRP3 and GSDMD inhibitors as therapeutics to counter excessive inflammation.

Keywords: NLRP3; SARS-CoV-2; gasdermins; interleukin-1β; pyroptosis.

Figure 1

Gasdermin family: tissue-specific signalling. Gasdermin A/B/C/D/E are expressed in distinct cell types and are activated by various signals, leading to inflammatory or non-inflammatory cell lysis. The upstream events of GSDMA cleavage are not well characterized (represented as ‘?’). GSDMA downregulation in gastric epithelial cells can lead to tumour formation. Proliferating tumour cells are recognized by effector T cells that release Granzyme A, which cleaves GSDMB in cancer cells leading to pore formation and tumour cell lysis. Furthermore, GSDMB can also be activated by Caspase 1 or 3 downstream of inflammasome formation or apoptosis, leading to pyroptosis. GSDMC is activated by Caspase 8 downstream of apoptosis, linking apoptosis to pyroptosis. GSDMD is the best characterized GSDM effector molecule, cleaved downstream of inflammasome activation, leading to pyroptosis. Similar to GSDMC, GSDME links apoptosis to pyroptosis subsequent to cleavage by Caspase 3 in apoptotic cells. (Created with BioRender.com on 7 May 2022).

Figure 2

NLRP3 inflammasome activation by SARS-CoV-2. The NLRP3 inflammasome can be primed by SARS-CoV-2 proteins spike and envelope, and in its opsonized form by activating the ACE-2, TLR-2, and complement receptors, respectively. SARS-CoV-2-infected cells upregulate ACE-2 receptor expression, rendering these cells more sensitive to SARS-CoV-2 response. Activation of these receptors leads to NFκB-mediated Nlrp3 gene transcription and translation. The NLRP3 inflammasome can form in response to ROS generation in SARS-CoV-2-infected cells, via potassium efflux through SARS-CoV-2 Orf3a-generated pores, or via direct interaction with the SARS-CoV-2 proteins orf8a and nucleoprotein. SARS-CoV-2 is capable of NLRP3 inflammasome inhibition via NS1 and NS13 proteins, as well as through inhibition of autophagy, a general NLRP3 trigger. Therapeutic potential lies in the inhibition of the effector molecule IL-1β via canakinumab or anakinra, as well as inhibition of the NLRP3 accessory protein BTK by ibrutinib. (Created with BioRender.com on 13 April 2022).