A single <i>Citrobacter rodentium</i> infection in Pink1 knockout and wildtype mice leads to regional blood-brain-barrier perturbation and limited microglial activation without dopamine neuron axon terminal loss

Abstract A growing body of research suggests a link between immune system activation and the development of Parkinson’s disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can induce PD-like motor dysfunction in Pink1 knockout (KO) mice, along with immune cell infiltration into the brain. To better understand mechanisms underlying immune-mediated brain attack in this model, we tested whether mild infections are sufficient to increase blood-brain barrier (BBB) permeability and trigger brain inflammation. Pink1 wild-type (WT) and KO mice were infected with C. rodentium , and gadolinium-enhanced magnetic resonance imaging (MRI) was performed at days 13 and 26 post-infection to assess BBB integrity. Quantitative MRI analysis revealed increased BBB permeability at day 26 in both WT and KO mice, particularly in the striatum, dentate gyrus, somatosensory cortex, and thalamus. Notably, this permeability was not associated with changes in tight junction protein expression or dopamine system markers in the striatum at either time point. However, persistent microglial activation was observed at day 26 post-infection, along with elevated levels of inflammatory mediators such as eotaxin, IFN-γ, CXCL9, IL-17, and MIP-2 in the striatum. Additionally, serum levels of IL-17 and CXCL1 were increased in infected Pink1 KO mice. Flow cytometry revealed neutrophil infiltration in the brain at day 26 post-infection. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. These findings support the hypothesis that even mild gastrointestinal infections can increase BBB permeability, disrupt brain homeostasis, and promote chronic neuroinflammation. In genetically susceptible individuals, such as those with Pink1 deficiency, this may represent a first hit that contributes to subsequent induction of PD pathology with aging. Author summary We hypothesize that immune system activation is linked to the development of Parkinson’s disease (PD). Previous work revealed that repeated gastrointestinal infections with Citrobacter rodentium causes PD-like symptoms and immune cell invasion in the brain of Pink1 knockout (KO) mice. In the current study, we tested whether a single mild gut infection alters blood-brain barrier (BBB) permeability and causes brain inflammation. We infected Pink1 WT and KO mice with Citrobacter rodentium and used gadolinium-enhanced MRI to detect BBB permeability changes at 13- and 26-days post-infection. Results showed increased BBB permeability in specific brain regions at 26 days. While tight-junction and dopamine (DA)-related proteins remained unchanged, we observed altered expression of synaptic genes, chronic microglial activation, elevated inflammatory markers, and neutrophil infiltration in the brain. Our findings suggest that even mild gastrointestinal infections can increase BBB permeability, potentially enabling immune cell infiltration into the brain and exacerbating pathways implicated in the development of PD, particularly among individuals with genetic risk factors.

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