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

Parkinson's disease (PD) is increasingly recognized as a neurological disorder characterized not only by neurodegeneration but also by chronic immune dysregulation across the lifespan. Although the initiating events underlying PD remain unclear, accumulating evidence suggests that inflammatory processes may contribute to disease susceptibility and progression. Mutations in leucine-rich repeat kinase 2 (LRRK2), particularly the gain-of-function G2019S variant, represent the common genetic cause of familial PD and have been implicated in immune regulation and infection susceptibility. To date, most research has focused on the effect of LRRK2 mutation in neurons and the contributions of G2019S-mediated kinase activity to neuronal toxicity, leaving the role of G2019S-mediated kinase activity in immune cell homeostasis and its contribution to PD pathogenesis largely unresolved.

Here, we used murine overexpression models of wildtype and G2019S variant of mouse Lrrk2 to examine how Lrrk2 G2019S shapes host defense across viral and bacterial infection models. We tested systemic sepsis and Escherichia coli infection to examine bacterial clearance. We followed up by testing macrophage responses to intracellular (Listeria monocytogenes) or primarily extracellular (Pseudomonas aeruginosa) bacteria. Finally, tested antibody-mediated immunity using influenza and cytotoxic T cell-mediated immunity using lymphocytic choriomeningitis virus (LCMV) infection.

We found that Lrrk2 G2019S overexpression enhanced survival and bacterial clearance during P. aeruginosa lung infection, whereas the same genotype worsened outcomes in polymicrobial sepsis, with increased mortality, pulmonary myeloid infiltration and a hematopoietic cell-intrinsic phenotype. During L. monocytogenes infection, Lrrk2 G2019S selectively reduced non-classical monocytes without altering disease progression. In influenza and LCMV infection, G2019S altered antigen-specific CD8⁺ T cell distribution without major changes in cell memory responses clinical severity.

Together, these data show that Lrrk2 G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner, uncoupling inflammatory magnitude from effective host defense. These results and previous work support a model in which the G2019S LRRK2 variant contributes to maladaptive inflammatory responses to specific infection challenges, providing insight into how lifetime immune perturbations may intersect with genetic susceptibility to influence lifetime infection risk.