A rewiring of the earliest immune events leading to T-cell mediated disease following intestinal microbial infection in a PINK1KO mouse model of Parkinson’s disease

Parkinson’s disease (PD) is characterized by a protracted period of non-motor symptoms, including gastrointestinal (GI) dysfunction, which can precede the development of cardinal motor dysfunction by decades. This long prodrome of disease is highly suggestive of immune cell involvement in the initiation of disease, but currently the field lacks robust modeling systems to study such mechanisms. The leading hypotheses for the origin of PD, known as the Braak’s hypothesis, states that pathology is first initiated in the GI tract due to environmental triggers, such as pathogens that enter the GI tract in genetically predisposed individuals. Our group has developed GI-targeted pathogen-induced PD mouse modeling systems (in PINK1 KO mice with gram negative bacterial infections) and found that T cells are a major player in driving PD-like motor symptoms at late stages following infection. Herein, we now map the initiating immune events at the site of infection at the earliest stages with the goal of shedding light on the earliest mechanisms triggering T cell-mediated pathological processes relevant to PD. Using unbiased single cell sequencing, we demonstrate that myeloid cells are the earliest dysregulated immune cell type in PINK1 KO infected mice (at 1-week post-infection) followed by a dysregulated T cell response shortly after (at 2 weeks post-infection). We find that these myeloid cells have an enhanced proinflammatory profile, are more mature, and develop enhanced capacity for antigen presentation. Using unbiased prediction analysis, our data suggests that cytotoxic T cells and myeloid cells are particularly poised for interacting with each other, and we identify possible direct cell-cell interaction pathways that might be implicated. How or if these early aberrant immune responses play a key role in initiating PD autoimmunity is the subject of further investigation.