Blastocystis sp. is a zoonotic protozoan with a broad host range, and its pathogenicity in humans has remained controversial. In this study, we observed neurocognitive impairments in mice following Blastocystis sp. infection, prompting us to investigate the mechanisms underlying these changes. Transcriptomic analysis of brain tissue revealed significant changes in the expression of several Neurocognitive Deficits -associated genes, most notably a marked downregulation of the nuclear receptor NR4A1. These findings were validated and confirmed using Western blot, immunofluorescence, and immunohistochemical analyses. While in vitro infection of BV2 microglial cells with Blastocystis sp. revealed activation of the IL-17-p38 MAPK-NR4A1 signaling axis, in vivo administration of a p38 inhibitor in infected mice ameliorated motor and cognitive deficits, demonstrating that this signaling cascade mediates neuropathology in mouse brain following the parasite infection. This finding indicates that Blastocystis sp. infection induces IL-17 overexpression in both the gut and brain, resulting in the activation of the p38 MAPK pathway. This subsequently leads to significant NR4A1 downregulation and, ultimately, results in Neurocognitive Impairment behavioral phenotypes in mice. This study reveals a novel mechanism whereby Blastocystis sp. infection induces cognitive and motor deficits through activation of the p38 MAPK-NR4A1 pathway in brain tissue, offering a potential therapeutic target for future interventions.
Yang et al. (Tue,) studied this question.