Durable interferon-linked blood signatures in COVID-19 convalescence: a longitudinal pre/post infection cohort study

Methods

Adults were sampled longitudinally with specimens collected before SARS-CoV-2 infection (T0) and at ~3 months (T1) and ~6 months (T2) post-infection; COVID-19–naïve controls were sampled across matched timepoints. Prior infection was determined using a multiplex anti-nucleocapsid IgG assay that spans multiple variant antigens. Whole-blood RNA-seq (PAXgene) was analyzed with DESeq2 using models that incorporated time point and participant.

To prioritize infection-linked changes, genes differentially expressed over time in controls were identified and excluded from COVID-19 timepoint comparisons. Pathways were evaluated by gene set enrichment analysis. Results: After excluding control-associated genes, COVID-19 convalescence remained associated with marked transcriptional remodeling (T1 vs T0: 955 genes; T2 vs T0: 772 genes; P<0.05) and persistent pathway-level changes.

Interferon-α and interferon-γ signatures were enriched at both T1 and T2, and a core set of interferon-associated genes remained elevated across convalescence. Conclusions: SARS-CoV-2 infection is followed by durable whole-blood immune-defense programs, including persistent interferon signaling, detectable up to 6 months post-infection. These sustained signatures support a model of prolonged post-infectious immune activation that may contribute to extended thromboinflammatory risk.