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. SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.
【저자키워드】 Infection, Viral host response, Inflammasome, 【초록키워드】 COVID-19, Cytokine storm, Cytokines, Inflammatory responses, IL-6, SARS-COV-2 infection, severity, COVID-19 severity, Proinflammatory response, Sepsis, cytokine, Acute inflammation, Lung injury, NLRP3 inflammasome, Protein, Viral, mice, hyperinflammation, N protein, death, SARS-CoV-2 N protein, caspase-1, proinflammatory cytokines, Mouse models, inhibitor, mechanism, cytokine production, binding, NLRP3, IL-1β, Interaction, Inflammatory response, inflammasomes, specific inhibitor, Proinflammatory cytokine, Activation, maturation, severe symptoms, cultured cells, NLRP3 inflammasome assembly, shown, resulting, blocked, cultured cell, facilitate, activated, interact, promote, induce, reveal, accelerate, aggravate, severe symptom, ASC, with COVID-19, 【제목키워드】 Activation, promote, induce,