COVID-19 patients with high TNF/IFN-y levels show hallmarks of PANoptosis, an inflammatory cell death

TNF and IFN-y trigger cell damage during SARS CoV-2 infection; these cytokines can induce senescence and a cell death process called PANoptosis. This study included 138 vaccine-naive COVID-19 patients, who were divided into four groups (Gp) according to the plasma level of TNF and IFN-y (High [Hi] or Normal-Low [No-Low]), Gp 1: TNFHi/IFNyHi; Gp 2: TNFHi/IFNyNo-Low; Gp 3: TNFNo-Low/IFNyHi; and Gp 4: TNFNo-Low/IFNyNo-Low. Thirty-five apoptosis-related proteins and molecules related to cell death and senescence were evaluated. Our results showed that groups did not display differences in age and comorbidities. However, 81% of the Gp 1 patients had severe COVID-19, and 44% died. Notably, the p21/ CDKN1A was increased in Gp 2 and Gp 3. Moreover, Gp 1 showed higher TNFR1, MLKL, RIPK1, NLRP3, Caspase 1, and HMGB-1 levels, suggesting elevated TNF and IFN-y levels simultaneously activate diverse cell death pathways because it is not observed when only one of these cytokines is increased. Thus, high TNF/IFN-y levels are predominant in severe COVID-19 status, and patients display cell alterations asso-ciated with the activation of diverse cell death pathways, including a possible senescent phenotype. (c) 2023 The Authors. Published by Elsevier Masson SAS on behalf of Institut Pasteur. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).