Chronic urinary tract infections cause persistent microglial changes in a humanized ɑ-synuclein mouse model

BACKGROUND: Urinary tract infections (UTIs) have recently been linked to the onset of multiple synucleinopathies including Parkinson's disease (PD) and multiple system atrophy (MSA). UTIs are more common in people with PD or MSA, than in the general population and within these patient groups the incidence of UTIs is evenly distributed between men and women. UTIs are especially common during disease, but also in the years before clinical diagnosis. OBJECTIVE: The mechanisms by which UTIs may contribute to the development and progression of PD or MSA are not well understood. In this work, we evaluate the neuroinflammatory effects of recurrent UTIs on the brain. METHODS: In a humanized mouse model of ɑ-synuclein, we find that repeated administration of uropathogenic E. coli result in sustained UTIs, or a non-resolving chronic UTI phenotype with persistent bacteriuria. Using this model, we investigate the effects of repeated chronic UTIs on neuroinflammation and synucleinopathy in the brain. RESULTS: Recurrent UTIs lead to behavioral motor changes and are accompanied by persistent neuroinflammatory changes in multiple brain areas. Affected regions with microglial changes involve multiple lower brainstem areas responsible for sickness behavior, including the dorsal vagal complex, and the cingulate cortex. CONCLUSIONS: These results suggests that recurrent UTIs can have lasting impact on the brain, and it warrants further investigation of the potential role of UTIs in the disease progression of synucleinopathies and related neurological disorders.