Abstract
Dengue virus (DENV) infection remains a critical global health threat, with DENV-2 being the most virulent serotype capable of causing lethal dengue hemorrhagic fever (DHF), a severe complication characterized by plasma leakage and hemorrhagic manifestations. While the search for viral receptors and immunocompetent animal models has persisted since the first recorded outbreak in 1779, significant gaps remain. Here, we establish the first immunocompetent murine model of DHF with intact innate/adaptive immunity by generating hTim4-transgenic C57BL/6J mice. This model recapitulates fatal DHF complications seen in humans, including systemic hemorrhage, dengue encephalitis and intestinal ischemia/gangrene. Integrated single-cell RNA sequencing and spatial transcriptomics analysis of hemorrhagic gut lesions demonstrated that DENV-2 infection induces Syk protein overexpression, leading to enhanced Th2 cytokine secretion and impaired hemostatic regulation. This cascade enhances vascular permeability, promotes plasma leakage, and drives multiorgan hemorrhage, a mechanism corroborated by parallel analyses of human DHF tissues. Critically, Th2-biased cytokine storm mirrors clinical findings in severe human dengue cases. Our work not only identifies hTim4 as a functional DENV-2 receptor but also provides a mechanistically grounded platform for DHF pathogenesis studies, bridging critical gaps between preclinical models and human immunopathology.