Receptor-mediated mechanisms underlying neurological complications in COVID-19: from viral entry to neuroinflammation

Abstract

Neurological complications of COVID-19 encompass acute syndromes and persistent post-acute sequelae, yet their mechanistic basis remains incompletely defined. Integrated clinical, neuropathological, neuroimaging, and molecular evidence indicates that SARS-CoV-2–associated neurological injury is driven predominantly by receptor-mediated immune and vascular mechanisms rather than widespread productive central nervous system infection. Angiotensin-converting enzyme 2 (ACE2) remains the principal viral entry receptor, while neuropilin-1 (NRP1) facilitates neurovascular and olfactory access in specific contexts. In contrast, CD147 and dipeptidyl peptidase-4 (DPP4) appear to exert indirect modulatory roles through endothelial dysfunction and immune activation rather than acting as dominant neurotropic entry receptors. Toll-like receptors, particularly TLR2, TLR4, and TLR7, amplify neuroinflammatory signaling and contribute to blood–brain barrier disruption, microvascular injury, and sustained microglial activation. Cerebrospinal fluid biomarkers and neuroimaging findings consistently support a dual-pathway model combining limited direct viral presence with predominant immune-mediated injury. Current therapeutic strategies targeting receptor-mediated entry and neuroinflammation remain largely investigational, underscoring the need for biomarker-guided and phase-specific interventions. These findings refine the mechanistic framework of NeuroCOVID and identify translational priorities for acute and long-term neurological management.