Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner

Abstract

The Lrrk2 gene modulates the course of infections in mice in a sex-dependent manner. Lrrk2ing in the shadows The leucine-rich repeat kinase-2 (LRRK2) gene has been associated with Parkinson’s disease, leprosy, and Crohn’s disease. We examined whether Lrrk2 plays a role in virulent infections. In mice carrying different versions of Lrrk2, we found that Lrrk2 altered the course of bacterial and viral infections by modulating inflammation. Animals expressing the Parkinson’s disease–linked p.G2019S Lrrk2 mutation showed reduced replication of a bacterial pathogen. During viral encephalitis, the p.G2019S Lrrk2 mutation worsened survival in mice, predominantly in females. Animals with viral encephalitis expressing a variant that blocked Lrrk2’s enzyme function showed improved survival. Lrrk2 may modulate the course of microbial infections in a manner that depends on mouse genotype, sex, and the type of pathogen. Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson’s disease, leprosy, and Crohn’s disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways. First, adult mice were intravenously inoculated with Salmonella typhimurium, resulting in sepsis. Second, newborn mouse pups were intranasally infected with reovirus (serotype 3 Dearing), which induced encephalitis. In both mouse models, wild-type Lrrk2 expression was protective and showed a sex effect, with female Lrrk2-deficient animals not controlling infection as well as males. Mice expressing Lrrk2 carrying the Parkinson’s disease–linked p.G2019S mutation controlled infection better, with reduced bacterial growth and longer animal survival during sepsis. This gain-of-function effect conferred by the p.G2019S mutation was mediated by myeloid cells and was abolished in animals expressing a kinase-dead Lrrk2 variant, p.D1994S. Mouse pups with reovirus-induced encephalitis that expressed the p.G2019S Lrrk2 mutation showed increased mortality despite lower viral titers. The p.G2019S mutant Lrrk2 augmented immune cell chemotaxis and generated more reactive oxygen species during virulent infection. Reovirus-infected brains from mice expressing the p.G2019S mutant Lrrk2 contained higher concentrations of α-synuclein. Animals expressing one or two p.D1994S Lrrk2 alleles showed lower mortality from reovirus-induced encephalitis. Thus, Lrrk2 alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.