Pilot proteomic analysis of immune dysregulation in dengue with prior SARS-CoV-2 infection

In regions where dengue and COVID-19 co-circulate, cross-reactive antibodies elicited by SARS-CoV-2 may exacerbate dengue severity. This exploratory, cross-sectional, observational pilot study evaluated whether prior SARS-CoV-2 exposure modulated dengue pathogenesis through proteomic profiling and in vitro assays, identifying putative biomarkers and immune pathways for further validation.

Eighteen participants from Oaxaca, Mexico, were prospectively stratified into four cohorts: healthy controls (CG), dengue with anti-SARS-CoV-2 IgG (NS1/SARS_IgG), dengue with both anti-SARS-CoV-2 and anti-dengue IgG (NS1/SARS-DENV_IgG), and dengue with anti-dengue IgG only (NS1/DENV_IgG). The serum levels of IL-6 and C-reactive protein (CRP) were quantified, and proteomic analysis was performed using label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). In vitro antibody-dependent enhancement (ADE) assays were performed using the DENV-1 and K562 cells.

The NS1/DENV_IgG group exhibited the most severe clinical presentation, including 39 °C fever and 50% thrombocytopenia. In contrast, the NS1/SARS-DENV_IgG group presented milder symptoms. IL-6 and CRP concentrations peaked in the NS1/SARS_IgG group (18.3 ± 15.6 pg/mL and 51.6 ± 29.6 mg/L, respectively). Proteomic profiling identified 279 high-confidence proteins and 18 differentially expressed proteins (DEPs). The NS1/SARS-DENV_IgG group showed enrichment in the complement/coagulation pathways (p = 0.016) and TGF-β signaling (p = 0.022). DEPs, including thrombospondin-1 and PRG2, have been implicated in Th2 polarization and ADE-like immune dysregulation. ADE assays confirmed that anti-SARS-CoV-2 serum enhanced DENV replication in vitro.

Prior SARS-CoV-2 exposure may potentiate dengue severity via cross-reactive antibody-mediated immune modulation, skewing toward Th2 responses and enhancing viral replication. These findings suggest novel candidate biomarkers for stratifying the dengue risk in co-endemic regions. However, the study's exploratory nature, small cohort (n = 18), pooled proteomic methodology, and limited clinical characterization necessitate validation in larger longitudinal studies.