Enterovirus A71 neuroinvasion: central nervous system entry, blood–brain barrier dynamics, and multistage constraints

Enterovirus A71 (EV-A71) is an important cause of severe neurological complications of hand, foot, and mouth disease in children. Most infections remain confined to peripheral sites, whereas only a small proportion progress to central nervous system (CNS) disease, and the mechanisms underlying this transition remain incompletely understood. Here, we reappraise EV-A71 neuropathogenesis as a multistage process comprising peripheral replication, systemic dissemination, CNS entry, establishment of productive CNS infection, and subsequent tissue injury. This distinction is important because these events are mechanistically connected but not interchangeable. Current evidence supports both neurovascular and peripheral neural routes of CNS entry, although the nature and strength of the supporting evidence differ. Human-derived blood–brain barrier (BBB) models demonstrate that EV-A71 and virus-associated carriers can engage and cross neurovascular interfaces, whereas temporal studies in animals, perturbation of axonal transport, and compartmentalized neuronal models provide stronger causal support for retrograde axonal transport once the virus has accessed peripheral nerves. These findings establish mechanistic feasibility, but the timing, necessity, and relative contribution of each route during natural infection in children remain unresolved. We further emphasize that BBB crossing is not synonymous with BBB disruption, and that CNS entry does not necessarily result in productive CNS infection. On this basis, we propose a multistage progression-constraint model, in which progression to severe neurological disease requires EV-A71 to overcome distinct constraints imposed by tissue context, viral properties, and host factors at successive stages. This framework provides a testable explanation for why most infections remain peripheral while only a minority progress to severe neurological disease, and highlights the need for longitudinal clinical studies and directly comparable experimental models to identify where disease trajectories first diverge.