Enhanced early IgG-mediated complement deposition in the development of chronic chikungunya virus disease

<jats:p>Chikungunya virus (CHIKV) is an arthritogenic alphavirus that has spread globally and caused significant outbreaks. While CHIKV disease often resolves following acute infection, individuals can progress to chronic CHIKV disease (CCD) characterized by persistent severe joint pain. Antibodies, especially IgG, help clear CHIKV through neutralization and Fc effector functions. Previous studies have associated CCD with a poor neutralizing antibody response. However, the role of Fc effector functions in the development of CCD remains unclear. Here, purified IgG from post-acute CHIKV-immune human serum samples that either resolved CHIKV disease or developed chronic symptoms was evaluated for IgG neutralization, binding characteristics, and Fc effector functions to correlate antibody characteristics with disease progression and identify antibody biomarkers for CCD. Resolution of CHIKV disease was associated with higher levels of CHIKV-specific IgG and IgG1 and stronger CHIKV neutralization. Fc effector function analysis showed enhanced IgG-mediated complement deposition on infected cells in individuals who developed chronic disease; while, those who recovered had elevated complement components in their serum. Overall, these findings suggest that localized activation of the classical complement pathway at sites of infection, rather than systemic complement activity, may contribute to ongoing inflammation and immune dysregulation associated with CCD.</jats:p>