Elucidating how infection shapes neurodegenerative disease at the brain border

Objective

Parkinson’s disease (PD) is the fastest-growing neurodegenerative disease worldwide, characterized by the accumulation of α-synuclein (αSyn). Evidence suggests two potential origins of αSyn pathology: brain-first or body-first initiation, with infection as possible trigger. Epidemiological studies implicate influenza infection in increasing the risk of developing PD, but the precise cellular mechanisms remain unclear. I propose that border-associated macrophages (BAMs), residing at the interface between the brain and periphery, are key to this question. BAMs are pivotal regulators of neuroimmune responses at the brain borders, capable of sensing and responding to peripheral inflammatory cues. During brain viral infections, they promote immune cell recruitment and limit viral spread, while αSyn overexpression induces neuroinflammation, with BAM depletion reducing dopaminergic neurodegeneration. I hypothesize that following influenza infection, BAMs sustain cytokine production and immune cell recruitment, which over time may promote neuroinflammation, αSyn propagation, and neurodegeneration in PD. Specifically, my research objectives are to: 1. Characterize the phenotype and function of brain border immune populations in mouse models of brain-first vs body-first PD. 2. Determine how BAMs respond to influenza infection and whether this affects neurodegeneration later in life. 3. Identify peripheral immune signatures in prodromal PD patients stratified by severe infection, to detect potential populations trafficking to the brain and increasing PD risk. By combining my expertise in viral immunology with Dr. De Schepper’s PD research and Dr. Delputte’s virology expertise, this interdisciplinary project aims to move beyond the current state-of-the-art to elucidate how influenza infection increases PD risk at the brain borders.