TNF/IFN-γ Co-Signaling Induces Differential Cellular Activation in COVID-19 Patients: Implications for Patient Outcomes.

TNF and IFN-γ are key proinflammatory cytokines implicated in the pathophysiology of COVID-19. Toll-like receptor (TLR)7 and TLR8 are known to recognize SARS-CoV-2 and induce TNF and IFN-γ production. However, it is unclear whether TNF and IFN-γ levels are altered through TLR-dependent pathways and whether these pathways mediate disease severity during COVID-19. This study aimed to investigate the association between TNF/IFN-γ levels and immune cell activation to understand their role in disease severity better. We enrolled 150 COVID-19 patients, who were classified by their systemic TNF and IFN-γ levels (high (H) or normal-low (N-L)) as TNF ^H IFNγ ^H , TNF ^H IFNγ ^N-L , TNF ^N-L IFNγ ^H , and TNF ^N-L IFNγ ^N-L . Compared to patients with TNF ^N-L IFNγ ^N-L , patients with TNF ^H IFNγ ^H had high systemic levels of pro- and anti-inflammatory cytokines and cytotoxic molecules, and their T cells and monocytes expressed TNF receptor 1 (TNFR1). Patients with TNF ^H IFNγ ^H presented the SNP rs3853839 to TLR7 and increased levels of MYD88, NFκB, and IRF7 (TLR signaling), FADD, and TRADD (TNFR1 signaling). Moreover, critical patients were observed in the four COVID-19 groups, but patients with TNF ^H IFNγ ^H or TNF ^H IFNγ ^N-L most required invasive mechanical ventilation. We concluded that increased TNF/IFN-γ levels are associated with hyperactive immune cells, whereas normal/low levels are associated with hypoactivity, suggesting a model to explain that the pathophysiology of critical COVID-19 may be mediated through different pathways depending on TNF and IFN-γ levels. These findings highlight the potential for exploring the modulation of TNF and IFN-γ as a therapeutic strategy in severe COVID-19.