Histopathological Alterations and Dysregulation of Type I Interferon Signaling in the Human Cerebral Cortex During Severe Dengue.

Dengue virus (DENV) is a major arthropod-borne pathogen, endemic in over 100 countries and posing global health challenges. While innate immune responses and viral evasion mechanisms have been extensively studied in animal models and mononuclear cells, severe dengue can affect multiple tissues, including the central nervous system (CNS), leading to neurological manifestations. However, the CNS immune response remains poorly understood. This study analyzed molecules linked to innate immunity in CNS lesions from fatal dengue cases. Histopathological examination of the cerebral cortex revealed marked neuronal damage-chromatolysis, pyknotic nuclei-accompanied by microglial hyperplasia, white matter demyelination, perivascular inflammation, vascular congestion, vasogenic edema, and occasional hemorrhage or meningitis. DENV antigen was detected in endothelial cells of cortical and leptomeningeal vessels and in glial cells or macrophages. Immunohistochemistry revealed altered expression of innate immune markers: RIG-I was sparsely expressed, STING was absent, and IFN-α/β levels were reduced compared to controls. Notably, IRF2 expression was markedly elevated, with strong labeling in neurons, glial, and endothelial cells. These findings suggest an atypical pattern of immune activation in the CNS during severe dengue and highlight a potential role for IRF2 in modulating cerebral immune responses, offering new insights into the neuropathogenesis of dengue.