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

TNF and IFN-γ 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-naïve COVID-19 patients, who were divided into four groups (Gp) according to the plasma level of TNF and IFN-γ (High [Hi] or Normal-Low [No-Low]), Gp 1: TNFHi/IFNγHi; Gp 2: TNFHi/IFNγNo-Low; Gp 3: TNFNo-Low/IFNγHi; and Gp 4: TNFNo-Low/IFNγNo-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-γ levels simultaneously activate diverse cell death pathways because it is not observed when only one of these cytokines is increased. Thus, high TNF/IFN-γ levels are predominant in severe COVID-19 status, and patients display cell alterations associated with the activation of diverse cell death pathways, including a possible senescent phenotype.

Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality.

Overproduction of inflammatory cytokines is a keystone event in COVID-19 pathogenesis; TNF and its receptors (TNFR1 and TNFR2) are critical pro-inflammatory molecules. ADAM17 releases the soluble (sol) forms of TNF, TNFR1, and TNFR2. This study evaluated TNF, TNFRs, and ADAM17 at the protein, transcriptional, and gene levels in COVID-19 patients with different levels of disease severity. In total, 102 patients were divided into mild, moderate, and severe condition groups. A group of healthy donors (HD; n = 25) was included. Our data showed that solTNFR1 and solTNFR2 were elevated among the COVID-19 patients (p < 0.0001), without increasing the transcriptional level. Only solTNFR1 was higher in the severe group as compared to the mildly ill (p < 0.01), and the level was higher in COVID-19 patients who died than those that survived (p < 0.0001). The solTNFR1 level had a discrete negative correlation with C-reactive protein (p = 0.006, Rho = -0.33). The solADAM17 level was higher in severe as compared to mild disease conditions (p < 0.01), as well as in COVID-19 patients who died as compared to those that survived (p < 0.001). Additionally, a potential association between polymorphism TNFRSF1A:rs767455 and a severe degree of disease was suggested. These data suggest that solTNFR1 and solADAM17 are increased in severe conditions. solTNFR1 should be considered a potential target in the development of new therapeutic options.