Monocyte-associated C1q upregulation and complement activation contribute to vascular endothelial and multi-organ injury in severe dengue.

Abstract

Dengue virus (DENV) infection causes a broad spectrum of clinical manifestations, ranging from self-limiting dengue fever (DF) to life-threatening severe dengue (SD). Increased vascular permeability and endothelial dysfunction are hallmarks of SD and contribute to plasma leakage, shock, and multi-organ injury, yet the underlying mechanisms remain incompletely understood. Here, we integrated dynamic bulk and single-cell RNA sequencing data from peripheral blood mononuclear cells (PBMCs) of dengue patients at different disease stages to investigate the mechanisms associated with disease progression. Complement-related signatures were prominently altered in patients with dengue with warning signs (DWS) and SD, with monocytes emerging as a major cellular source of increased C1Q genes (C1QA, C1QB, and C1QC) expression. These findings implicated monocyte-derived C1q and classical complement pathway activation in dengue progression. Using a severe dengue mouse model, we further demonstrated systemic complement activation and deposition of the terminal complement effector membrane attack complex (MAC), which was associated with microvascular endothelial damage and multi-organ injury. Importantly, inhibition of the classical complement pathway with C1INH (C1 esterase inhibitor) significantly alleviated vascular barrier dysfunction and multi-organ injury in severe dengue mice. Collectively, our findings identify monocyte-derived C1q and dysregulated classical complement activation as important contributors to vascular endothelial and multi-organ injury in SD and suggest that targeting the classical complement pathway may represent a potential therapeutic strategy for severe dengue.