LRRK2 G2019S reprograms innate and adaptive immunity to drive context-dependent host defense outcomes

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• Parkinson's disease (PD) involves neurodegeneration and immune dysregulation.
• LRRK2 mutations, especially G2019S, are linked to PD and immune function.
• The role of G2019S kinase activity in immune cell homeostasis is largely unknown.

Purpose of the Study:

• To investigate how LRRK2 G2019S affects host defense against various infections.
• To examine the impact of LRRK2 G2019S on innate and adaptive immune responses.

Main Methods:

• Murine models overexpressing wildtype and G2019S Lrrk2.
• Testing bacterial infections (E. coli, P. aeruginosa, L. monocytogenes) and viral infections (influenza, LCMV).
• Assessing host survival, bacterial clearance, immune cell responses, and T cell-mediated immunity.

Main Results:

• G2019S enhanced survival and bacterial clearance in P. aeruginosa lung infection.
• G2019S worsened outcomes in sepsis, increasing mortality and myeloid infiltration.
• G2019S altered monocyte populations and CD8+ T cell distribution without significantly changing disease severity in viral models.

Conclusions:

• LRRK2 G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner.
• The G2019S variant can lead to maladaptive inflammatory responses to specific infections.
• This provides insight into how genetic susceptibility and immune perturbations intersect to influence infection risk in PD.