Spontaneous, persistent T-cell dependent IFN-γ release in patients who progress to Long COVID

After acute infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a significant proportion (0.2 – 30%) of patients experience persistent symptoms beyond 12 weeks, termed Long COVID. Understanding the mechanisms which cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic and monitoring purposes is urgently required. Persistently high levels of IFN-γ were detected from peripheral blood mononuclear cells (PBMCs) of Long COVID patients using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in Long Covid patients, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. IFN-γ release was CD8+ T cell mediated and dependent on MHC-I antigen presentation by CD14+ cells. After vaccination, a significant decrease in IFN-γ correlated with resolution of some Long COVID symptoms. Our study highlights a key mechanism underlying Long COVID, enabling the search for biomarkers and therapeutics in patients with Long COVID.