The Parkinson's disease-linked G2019S mutation of LRRK2 increases NADPH oxidase-2 activity in neutrophils for superior control of bacterial infections.

Allelic variants in the leucine-rich repeat kinase-2 (LRRK2) gene are linked to Parkinson's disease, Crohn's disease and leprosy; however, a consensus role of LRRK2 in infection has not yet emerged. Parkinson's disease-linked p.G2019S mutation of LRRK2 results in increased kinase activity. We evaluated the impact of the p.G2019S mutation during the infection of mice with Salmonella typhimurium (ST) or Listeria monocytogenes. We demonstrate that the p.G2019S mutation promotes the phosphorylation of the p40phox and p47phox subunits of the NADPH oxidase-2 complex in the cytosol of neutrophils, leading to their relocation to lysosomes for enhanced bacterial control. Activation of Cathepsin B, Rab10 or PKC was not modulated by p.G2019S. Activation of the cytosolic subunits of NADPH oxidase-2 subunits was inhibited by the virulence factor SifA, which promotes the phagosomal localization of ST. Deletion of SifA resulted in an even greater effect of the p.G2019S mutation on the control of ST by neutrophils. These results suggest a mechanism by which the p.G2019S mutation promotes better control of infections at the cost of excessive tissue damage via NADPH oxidase-2 activity under chronic inflammatory conditions.