The assembly of neutrophil inflammasomes during COVID-19 is mediated by type I interferons

• DOI: 10.1371/journal.ppat.1012368
• Publication Date: 2024-08-22T17:28:43Z
• Authors: Luz E. Cabrera; Suvi T. Jokiranta; Sanna Mäki; Simo Miettinen; Ravi Kant; Lauri Kareinen; Tarja Sironen; Jukka-Pekka Pietilä; Anu Kantele; Eliisa Kekäläinen; Hanna Lindgren; Pirkko Mattila; Anja Kipar; Olli Vapalahti; Tomas Strandin
• Keywords: Male; Adult; QH301-705.5; Neutrophils; Inflammasomes; 2405 Parasitology; 10184 Institute of Veterinary Pathology; Mice; 1311 Genetics; 1312 Molecular Biology; Humans; Animals; Biology (General); 2403 Immunology; SARS-CoV-2; 2404 Microbiology; COVID-19; RC581-607; Middle Aged; General medicine, internal medicine and other clinical medicine; Immunity, Innate; Mice, Inbred C57BL; Biomedicine; Interferon Type I; 2406 Virology; 570 Life sciences; biology; Female; Immunologic diseases. Allergy; Research Article

The severity of COVID-19 is linked to excessive inflammation. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation, but their role in COVID-19 pathophysiology remains poorly understood. We conducted transcriptomic profiling of neutrophils obtained from patients with mild and severe COVID-19, as well as from SARS-CoV-2 infected mice, in comparison to non-infected healthy controls. In addition, we investigated the inflammasome formation potential in neutrophils from patients and mice upon SARS-CoV-2 infection. Transcriptomic analysis of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, revealed a striking type I interferon (IFN-I) gene signature in severe COVID-19 patients, contrasting with mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 patients exhibited an immature neutrophil phenotype and lacked this IFN-I signature. Moreover, PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation, but reduced responsiveness to exogenous inflammasome priming. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes. These findings suggest a potential role for neutrophil inflammasomes in driving inflammation during severe COVID-19. Altogether, these findings open promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.