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Spontaneous NLRP3 inflammasome-driven IL-1-ß secretion is induced in severe COVID-19 patients and responds to anakinra treatment.
Bertoni, Arinna; Penco, Federica; Mollica, Hilaria; Bocca, Paola; Prigione, Ignazia; Corcione, Anna; Cangelosi, Davide; Schena, Francesca; Del Zotto, Genny; Amaro, Adriana; Paladino, Noemi; Pontali, Emanuele; Feasi, Marcello; Signa, Sara; Bustaffa, Marta; Caorsi, Roberta; Palmeri, Serena; Contini, Paola; De Palma, Raffaele; Pfeffer, Ulrich; Uva, Paolo; Rubartelli, Anna; Gattorno, Marco; Volpi, Stefano.
  • Bertoni A; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy.
  • Penco F; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Mollica H; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy.
  • Bocca P; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Prigione I; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Corcione A; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Cangelosi D; Clinical Bioinformatics Unit and Diagnostics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Schena F; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Del Zotto G; Department of Research and Diagnostics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Amaro A; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  • Paladino N; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Pontali E; Ente Ospedaliero Ospedale Galliera, Genova, Italy.
  • Feasi M; Ente Ospedaliero Ospedale Galliera, Genova, Italy.
  • Signa S; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy.
  • Bustaffa M; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Caorsi R; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • Palmeri S; DINOGMI, Università degli Studi di Genova, Genova, Italy.
  • Contini P; Department of Internal Medicine, University of Genoa and IRCCS IST-Ospedale San Martino, Genova, Italy.
  • De Palma R; Department of Internal Medicine, University of Genoa and IRCCS IST-Ospedale San Martino, Genova, Italy.
  • Pfeffer U; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  • Uva P; Clinical Bioinformatics Unit and Diagnostics, IRCCS Istituto Giannina Gaslini, Genova, Italy; Italian Institute of Technology, Genova, Italy.
  • Rubartelli A; Istituto Giannina Gaslini, Genova, Italy.
  • Gattorno M; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy. Electronic address: marcogattorno@gaslini.org.
  • Volpi S; UOSD Centro per le Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy; DINOGMI, Università degli Studi di Genova, Genova, Italy. Electronic address: stefanovolpi@gaslini.org.
J Allergy Clin Immunol ; 2022 Jul 11.
Article in English | MEDLINE | ID: covidwho-1991092
ABSTRACT

BACKGROUND:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained.

OBJECTIVES:

To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1ß, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes.

METHODS:

We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line.

RESULTS:

We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1ß in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation.

CONCLUSIONS:

These results provide further evidence that IL-1ß targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2022 Document Type: Article Affiliation country: J.jaci.2022.05.029

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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2022 Document Type: Article Affiliation country: J.jaci.2022.05.029