Molecular Pathogenesis of Dengue Virus Meningoencephalitis: Evidence and Working Hypotheses

Dengue virus (DENV) is classically regarded as a non-neurotropic systemic pathogen, yet severe neurological complications, most notably meningoencephalitis, are increasingly recognized. This review synthesizes the available evidence on the molecular determinants of DENV neuroinvasion and central nervous system (CNS) injury, indicating which steps are established and which remain hypothetical. Crossing of the blood–brain barrier is thought to involve secreted non-structural protein 1 (NS1), which degrades the endothelial glycocalyx, and together with matrix metalloproteinase-9 impairs endothelial junctions (the role of TLR4 is disputed), as well as monocyte-mediated trans-endothelial migration. Disease severity may be shaped by antibody-dependent enhancement (ADE) during secondary heterologous infection through extrinsic (enhanced viral entry) and intrinsic (suppressed antiviral signaling) mechanisms documented in peripheral myeloid cells and proposed here, by extrapolation, to operate in microglia, possibly counterbalanced by natural killer cell-mediated cytotoxicity. Elevated cerebrospinal fluid IL-6 and TNF-α indicate neuroinflammation; by extrapolation from other flaviviruses, microglial activation and impaired astrocytic glutamate clearance may converge on NMDA receptor-mediated excitotoxicity and neuronal apoptosis, a step not directly examined in dengue. As much of this model rests on peripheral, in vitro, animal, or other-flavivirus data, CNS-focused mechanistic studies are needed.