Decoding the lung-brain axis in influenza: from pulmonary infection to central nervous system injury

Influenza viruses are respiratory pathogens of the family Orthomyxoviridae. Among the four recognized types, influenza A virus (IAV) is the primary cause of seasonal epidemics and pandemics. Continuous antigenic drift facilitates immune evasion, whereas occasional antigenic shift drives the emergence of novel hemagglutinin (HA) and neuraminidase (NA) subtype combinations. Although influenza is primarily characterized by respiratory manifestations, it can also cause severe central nervous system (CNS) complications, including encephalitis, collectively referred to as influenza-associated encephalopathy (IAE), which is associated with poor clinical outcomes and remains frequently overlooked. The neurotropic potential of influenza viruses remains controversial. Although vaccination and antiviral therapies effectively reduce influenza-related morbidity and mortality, specific preventive and therapeutic strategies for influenza-associated CNS complications remain limited. This review synthesizes current evidence on the neuroinvasive characteristics of influenza viruses, including susceptibility factors, viral determinants, host responses, pathogenic mechanisms, therapeutic strategies, and prognostic indicators. Particular emphasis is placed on the mechanisms underlying CNS injury, including both direct viral invasion and indirect injury mediated by dysregulated immune and inflammatory responses. By integrating these emerging mechanistic insights, this review proposes a lung-brain axis framework to explain the bidirectional communication between pulmonary infection and neurological injury during influenza. This framework provides an updated perspective on the pathogenesis of IAE, identifies potential therapeutic targets, and may facilitate future studies aimed at improving early diagnosis, risk stratification, and the development of mechanism-based interventions.