SARS-CoV-2 triggers inflammasome-dependent release of pro-inflammatory cytokine IL-1β and pyroptosis, therefore, contributes to the huge inflammatory response observed in severe COVID-19 patients. Less is known about the engagement of inflammasome in neutrophils, main players in tissue injury and severe infection. We studied the activation of the inflammasome in neutrophils from severe COVID-19 patients and assessed its consequence in term of cells contribution to disease pathogenesis. We demonstrated that NLRP3 inflammasome is dramatically activated in neutrophils from severe COVID-19 patients and that the specific inhibition of NLRP3 reverts neutrophils' activation. Next, the stimulation of severe patients' neutrophils with common NLRP3 stimuli was not able to further activate the inflammasome, possibly due to exhaustion or increased percentage of circulating immature neutrophils. Collectively, our results demonstrate that the NLRP3 inflammasome is hyperactivated in severe COVID-19 neutrophils and its exhaustion may be responsible for the increased susceptibility to subsequent (and possibly lethal) infections. Our findings thus include a novel piece in the complex puzzle of COVID-19 pathogenesis.

Objective and design The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease. Methods To address this question, we performed an association study of NLRP1 , DPP9 , CARD8 , IL1B , and IL18 single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients. Results The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases. Conclusion Inflammasome genetic background contributes to individual response to SARS-CoV-2. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-022-01670-3.

Objective and design: The heterogeneity of response to SARS-COV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stand out as a good novel candidate as severity factor for Covid-19 disease. Methods: To address this question, we performed an association study of NLRP1, DPP9, CARD8, IL1B and IL18 single nucleotide variants (SNVs) in a cohort of 945 Covid-19 patients. Results: The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to Covid-19 severity, which could contribute to the excessive cytokine release reported in severe cases.