Infection-Induced Extracellular Vesicles Evoke Neuronal Transcriptional and Epigenetic Changes

Abstract

Infection with the protozoan Toxoplasma gondii induces changes in neurotransmission, neuroinflammation, and behavior, yet it remains elusive how these changes come about. In this study we investigated how norepinephrine levels are altered by infection. TINEV (Toxoplasma-induced neuronal extracellular vesicles) isolated from infected noradrenergic cells down-regulated dopamine ß-hydroxylase (DBH) gene expression in human and rodent cells. Here we report that intracerebral injection of TINEVs into the brain is sufficient to induce DBH down-regulation and distrupt catecholaminergic signalling. Further, TINEV treatment induced hypermethylation upstream of the DBH gene. An antisense lncRNA to DBH was found in purified TINEV preparations. Paracrine signalling to induce transcriptional gene silencing and DNA methylation may be a common mode to regulate neurologic function.

Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice

“…As a parasite that reproduces in cats as part of its life cycle, T. gondii impairs the innate fear of cat odor in rodents, increasing the chance that the parasite reaches its intermediate (feline) and permanent (larger animals, including humans) host (Kannan et al 2010, Vyas et al 2007, Webster et al 1994). Although the mechanisms by which T. gondii changes host behavior are not fully understood, recent studies showed that T. gondii infection in rodents profoundly decreases expression of DBH, reducing NE and elevating DA in the brain (Alsaady et al 2019, Tedford et al 2023). Our results provide additional evidence that the T. gondii -induced reduction of DBH may lead to suppression of defensive behaviors that would normally promote escape from a predator.…”