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 TNFIFNγ, TNFIFNγ, TNFIFNγ, and TNFIFNγ. Compared to patients with TNFIFNγ, patients with TNFIFNγ 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 TNFIFNγ 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 TNFIFNγ or TNFIFNγ 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.