Tissue-specific transcriptional epistasis between Prkn and Lrrk2 during mycobacterial infection.

PRKN (PARK2) and LRRK2 are susceptibility genes for Parkinson’s disease that also exert pleiotropic effects in inflammatory and mycobacterial diseases. Although each gene individually regulates innate immune pathways, their combined in vivo interaction during infection remains undefined. We hypothesized that Prkn and Lrrk2 exhibit systems-level epistasis in shaping host transcriptional responses to mycobacterial challenge. To test this, we analyzed single and double knockout mice to define baseline and infection-induced transcriptional programs following bacille Calmette-Guérin (BCG) infection. Lung and spleen tissues were assessed for bacterial burden and genome-wide gene expression. In the lung, deletion of Prkn and Lrrk2 affected overlapping immune pathways, and double knockout mice displayed non-additive modulation of infection-induced transcriptional networks, consistent with systems-level epistasis. In contrast, splenic responses were dominated by Lrrk2 deletion, indicating tissue-dependent genetic interaction. To determine whether these transcriptional effects extended to virulent mycobacteria, we examined Lrrk2-dependent responses during aerosol infection with Mycobacterium tuberculosis, revealing context-dependent pathway activation distinct from the BCG model. These findings demonstrate tissue- and pathogen-specific epistasis between Prkn and Lrrk2 at the level of host transcriptional network organization. Our results establish these genes as interacting regulators of antimycobacterial immune programs and provide a systems-genetic framework linking neurodegeneration-associated loci to host defense.