Objective: The mechanisms by which allelic changes in LRRK2 modulate the susceptibility to Parkinson’s disease, Crohn’s disease and leprosy remain unknown. We hypothesized that leucine-rich repeat kinase-2 (LRRK2) plays a key role in the innate immune response by mammalian hosts. We sought to test this hypothesis in infectious paradigms in vivo using genotypically modified mice and virulent pathogens.

Background: We and others have found that LRRK2 protein is highly abundant in immune cells and organs (Hakimi et al., 2011). Recent studies also suggested that endogenous Lrrk2 modifies inflammation in rodent brain following exposure to bacterial mimics and elevated SNCA expression.

Methods: We employed viral and bacterial infection paradigms using genotypically modified mice with no endogenous Lrrk2, carrying wild-type Lrrk2 (Tong et al., PNAS 2010) or mutant G2019S knock-in Lrrk2 (Herzig et al., HMG 2013).

Results: First, we inoculated newborn mice with a respiratory-enteric-orphan virus (‘reovirus’, serotype-3) applied to the nose pad (Gauvin et al., 2013). During the ensuing encephalitis, we detected more reovirus protein in Lrrk2-deficient mice than heterozygous and wild-type (WT) animals. The odds ratio for death from encephalitis in Lrrk2-deficient mice was 3.45 (p=0.002). In a bacterial sepsis model, we inoculated animals intravenously with Salmonella typhimurium, where Lrrk2 deficiency led to more colony forming units in solid organs of adult animals (p=0.01). In contrast, the Parkinson’s-linked mutant, Lrrk2 G2019S, lowered S. typhimurium burden and reovirus titres in acutely infected organs (including brain) from knock-in mice. Despite the lower viral burden, fewer G2019S Lrrk2 mice survived encephalitis. The odds ratio for death from encephalitis in all G2019S Lrrk2 animals was 1.46 and showed a sex bias (p=0.056).

Conclusions: We identified a systemic, anti-microbial effect for Lrrk2. Paradoxically, both Lrrk2 deficiency and the Parkinson’s-linked G2019S mutant worsened the outcome of a viral brain infection that was naturally acquired; the former reduced the host’s response, the G2019S mutation augmented it. We speculate that the risk association of LRRK2 alleles with three human diseases may be explained through altered regulation of innate immune responses following exposure to virulent microbes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-alleles-modify-host-response-to-microbial-infections/