Long term effects of respiratory infections on the meningeal immune brain axis

Context and rationale. Respiratory infections are increasingly recognised as triggers of persistent neurological and neuropsychiatric symptoms that extend beyond resolution of the acute disease. A broad range of infectious inducers including viruses and bacteria can initiate these processes. Among viral agents, influenza viruses and SARS CoV 2 responsible for COVID infections have highlighted the scale and persistence of post infection brain related symptoms. Clinical observations across respiratory infections indicate long lasting cognitive impairment, fatigue, mood disorders, sleep disruption and altered stress responses. Emerging evidence suggests that these outcomes are mediated in part through sustained immune dysregulation at the interface between the periphery, the meninges and the central nervous system. The meningeal immune compartment acts as a critical signalling hub linking systemic inflammation to brain function, yet its role in post infection long term conditions remains insufficiently characterised across biological, behavioural and social contexts.

Overall objective. The project aims to elucidate how respiratory infections caused by different microbial agents induce persistent alterations of the meningeal immune brain axis and how these changes contribute to long term neurological, cognitive and neuropsychiatric sequelae. By integrating immunology, neuroscience, epidemiology, clinical research, social sciences and data science, the project will generate mechanistic insight and translational tools to improve prevention, diagnosis, treatment and rehabilitation of brain related post infection conditions across heterogeneous populations.

Objective 1. Characterising long term changes in meningeal immune cell composition, activation states and signalling pathways following respiratory infections. This integrates longitudinal cohort data with deep immune and neurobiological profiling and links biological alterations to cognitive outcomes across different infectious triggers.

Objective 2. Identifying immune, inflammatory, imaging and neurobiological biomarkers associated with persistent brain dysfunction, symptom burden and recovery trajectories. Biomarker discovery will support patient stratification, early identification of individuals at risk and monitoring of treatment response.

Objective 3. Defining risk and resilience factors shaping long term outcomes following respiratory infections. Specific attention will be given to sex differences and hormonal influences, age, lifestyle factors, socioeconomic context and pre existing conditions. Down syndrome will be addressed as a sensitised human model of immune dysregulation and cognitive vulnerability, enabling mechanistic insight into susceptibility and resilience pathways relevant to the general population.

Objective 4. Identifying and informing preventive, therapeutic and rehabilitative strategies targeting post infection brain dysfunction. This includes prioritisation of pharmacological targets and repurposing opportunities for immune and neuro immune modulation, alongside evaluation of non pharmacological and rehabilitative interventions such as cognitive training, sleep and stress regulation and lifestyle based approaches. Evidence generated will support best practices for integration of post infection care into primary and specialised healthcare settings.

Methodological approach. The project will combine longitudinal clinical cohorts with advanced immune, neuroimaging and neurocognitive assessments, stratified by key biological and social factors including sex, age, lifestyle, socioeconomic context and pre existing conditions such as Down syndrome. Human studies will be complemented by pre clinical and computational approaches, using FAIR data practices, European research infrastructures and artificial intelligence to identify predictive patterns of disease progression and recovery.

Expected outcomes and impact. The project will establish a mechanistic framework linking respiratory infections to long term brain related symptoms, enabling earlier identification of at risk individuals, development of actionable biomarkers and improved prevention, treatment and rehabilitation strategies. These advances will support better quality of life, reduced disease burden and enhanced healthcare system preparedness.

Consortium and stakeholder engagement. The consortium will bring together expertise in neuro immunology, meninges biology, infectious diseases, neurology, psychiatry, endocrinology, Down syndrome research, epidemiology, social sciences, rehabilitation and data science. Clinical partners, biomarker experts and partners in drug repurposing and non pharmacological interventions will be central, with active involvement of patients, healthcare professionals, public authorities and innovative SMEs to ensure impact and translation.