IgA Dengue Virus NS1 Immune Complexes Are Associated with In Vitro Neutrophil Activation 2308886

Abstract

Abstract Introduction Dengue virus (DENV) causes ∼400 million infections annually, with severe disease occurring more frequently during heterologous secondary infections, partly due to antibody-dependent enhancement and heightened inflammation. While IgG responses have been extensively studied, the role of circulating IgA, particularly IgA targeting non-structural protein 1 (NS1), in modulating neutrophil activation remains poorly understood. IgA immune complexes (ICs) can engage Fc receptors on neutrophils and trigger effector functions such as neutrophil extracellular trap (NET) formation (NETosis), but their contribution to dengue immunopathogenesis has not been fully characterized. Methods Serum samples from DENV-seropositive individuals in Puerto Rico (n = 20) were evaluated for IgA and IgG recognition of recombinant DENV-2 NS1 and envelope (E) proteins by ELISA. Neutrophils isolated from healthy donors were stimulated for 6 hours with IgA-NS1 or IgG-NS1 immune complexes. NETosis was quantified using the Incucyte live cell imaging system. Correlation analyses were performed in GraphPad Prism. Results IgG recognized NS1 and E proteins at comparable levels, while IgA favored the recognition of NS1 over E protein. The mean NS1/E ratio was 1.09 for IgG (range 1.02—1.16) and 1.71 for IgA (range 1.18—2.10). NETosis demonstrated a stronger and more statistically significant association with IgA-NS1 ICs (R² = 0.42, p < 0.0001) when compared to IgG-NS1 complexes (R² = 0.15, p = 0.026). Conclusion Collectively, these findings suggest that IgA—NS1 immune complexes may serve as potential modulators of neutrophil-driven inflammation in dengue. This isotype-specific linkage to NETosis suggests a distinct immunopathogenic pathway that may be particularly relevant during heterologous DENV infection and merits further mechanistic and translational investigation. Funding Source R01AI153434 & U54MD007579 Topic Categories Viral Immunology (VIR)