SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

Pan Pan,Xin Chen,Wenbiao Wang,Yongkui Li,Pin Wan,Qiwei Zhang,Yaling Jia,Keli Chen,Geng Li,Mingfu Tian,Zhenwei Wang,Miaomiao Shen,Weiwei Ge,Zhiwei Lei,Feng Xiao,Zhen Luo,Zhenyang Yu,Meng Xu,Weijie Chen,Jing Zhang,Jun Wang,Jianguo Wu

doi:10.1038/s41467-021-25015-6

Abstract

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

Highlights

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19
As inflammasome-mediated mature IL1β induces the release of cytoplasmic proteins and factors, and plays an important role in initiating “cytokine storm”[18], we evaluated the effect of SARS-CoV-2 proteins on the production of mature IL-1β
Our results demonstrate that N protein induces IL-1β maturation and IL-6 production, and reveal that NLRP3 is required for N-induced IL-1β secretion and IL-6 production protein, thereby suggesting that N protein may play an important role in the activation of the NLRP3 inflammasome

Summary

Introduction

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are associated with COVID-19 severity. We show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. This study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses. SARS-CoV-2 infects human respiratory system and causes severe inflammatory responses[7,8]. Studies have reported that inflammasomes are induced upon SARS-CoV2 infection and are associated with COVID-19 severity[19,20].

Methods

Results

Conclusion