Distinct plasma proteome signature at 3 months post-COVID-19 infection irrespective of post-COVID condition

Persistent symptoms following SARS-CoV-2 infection are the hallmark of post-COVID condition (PCC), also referred to as long COVID. However, the underlying molecular mechanisms remain poorly understood. In this study, we employed data-independent acquisition mass spectrometry (DIA-MS)-based plasma proteomics to identify molecular alterations associated with PCC. DIA-MS proteomic analysis revealed a clear distinction between the plasma proteome of uninfected individuals and those previously infected with SARS-CoV-2, irrespective of PCC status. PCC samples demonstrated downregulation of the antioxidant protein peroxiredoxin 6 (PRDX6) and upregulation of oxidative stress-associated proteins, particularly vanin-1 (VNN1) and paraoxonase-3 (PON3). Additionally, individuals with PCC exhibited significantly elevated levels of six proteins-PCSK9, CST3, C1Q, CPB2, KNG1, and GAPDH-associated with glycolysis, complement and coagulation cascades, and inflammatory pathways. Validation by ELISA does not necessarily reflect the proteomics data suggesting the requirement for alternate methods of validation. Nonetheless, oxidative stress, as measured by 8-hydroxy-2'-deoxyguanosine (8-OHdG), further showed that PCC samples had significantly higher levels of DNA damage, compared with convalescent individuals. Antioxidant markers, including reduced and oxidized glutathione (GSH and GSSG), were significantly lower in PCC samples than in uninfected controls. Collectively, these findings indicate that plasma proteomic alterations persist for at least 3 months following SARS-CoV-2 infection, with additional disruptions in oxidative stress and inflammatory pathways characterizing individuals with PCC.