Interferon gene expression declines over time post-COVID infection and in long COVID patients.

Background: Interferons (IFNs) represent a first-line defense against viruses and other pathogens. It has been shown that an impaired and uncontrolled release of these glycoproteins can result in tissue damage and explain severe progression of coronavirus disease 2019 (COVID-19). However, their potential role in Long-COVID syndrome (LC) remains debateable.

Objectives: The objective of the present study is to shed further light on the possible role of IFNs (and related genes) gene expression patterns in the progression of COVID-19 and LC patients.

Methods: We carried out a multi-cohort study by analyzing the IFN gene expression patterns (using different IFN gene signatures) in five cohorts of acute COVID-19 ( = 541 samples) and LC patients ( = 188), and compared them to patterns observed in three autoimmune diseases (systemic lupus erythematous [ = 242], systemic sclerosis [ = 91], and Sjögren's syndrome [ = 282]).

Results: The data show that, while the interferon signatures are strongly upregulated in severe COVID-19 patients and autoimmune diseases, it decays with the time from symptoms onset and in LC patients. Differential pathway analysis of IFN-related terms indicates an over activation in autoimmune diseases (IFN-I/II) and severe COVID-19 (IFN-I/II/III), while these pathways are mostly inactivated or downregulated in LC (IFN-I/III). By analyzing six proteomic LC datasets, we did not find evidence of a role of IFNs in this condition.

Conclusion: Our findings suggest a potential role of cytokine exhaustion mediated by IFN gene expression inactivation as a possible driver of LC.