Elevated brain α-synuclein, phosphorylated-tau, and oxidative stress in mice that survived influenza A pneumonitis

Influenza virus infection increases the incidence of parkinsonism in humans. We have previously shown that allelic variants at the Parkinsons disease (PD)-linked Lrrk2 locus modulate host responses in vivo. Here, we asked whether Lrrk2 kinase activity alters disease outcomes in adult mice that survived a nasally acquired infection. We inoculated mice with the mouse adapted A/Fort Monmouth/1/1947 influenza A virus, serotype H1N1 (LD50, 2x103 plaque forming units), leading to pneumonitis. We found that neither the hyperkinase-active Lrrk2 p.G2019S knock-in mutant nor the kinase-dead Lrrk2 p.D1994S mutant altered the course of an acute H1N1 lung infection. We then probed for long-term effects of H1N1 pneumonitis on brain health by monitoring surviving mice for six weeks post-inoculation. Intriguingly, at this time point, when mice had recovered and showed no detectable viral proteins in the brain, levels of H2O2 and protein nitrotyrosination were significantly elevated in H1N1 survivors vs. mock-treated littermates. In addition, total -synuclein concentrations were increased in an infection-dependent manner but independent of the Lrrk2 genotype. Intriguingly, at the same timepoint, the ratio of phosphorylated-to-total tau (but not total tau itself) was significantly increased in the brains of H1N1-virus exposed Lrrk2 p.G2019S mice compared to wild-type animals. Our collective results demonstrate that a preceding pneumotropic influenza A virus infection can lead to a rise in several neurodegeneration-linked markers in the brains of surviving mice. The increased ratio of phosphorylated-to-total tau in Lrrk2 p.G2019S animals adds to the growing evidence of interactions between specific microbial pathogens and allelic variants at the Lrrk2 locus. The described outcomes in animals that survived an influenza A virus infection may be of relevance to the incidence of neurodegenerative diseases in ageing humans.