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 are wrought by the small percentage of neurons that are infected. In this study we investigated how neurotransmission is altered in uninfected neurons during infection by studying suppression of noradrenergic signalling. Noradrenergic signalling is central in modulating the neuroinflammatory response. Previous studies found decreased norepinephrine and down-regulation of the synthetic enzyme dopamine ß-hydroxylase (DBH) during chronic infection. Here, extracellular vesicles (ie. exosomes) were isolated from infected cultures that induced transcriptional gene silencing of DBH and DNA hypermethylation upstream of the DBH gene. Intracerebral injection of these extracellular vesicles induced DBH down-regulation in the locus coeruleus region of the brain and contained an antisense lncRNA. Thus, global changes invoked by signals released from infected neural cells may help explain the parasite-induced behavior changes. This novel form of paracrine signalling may apply to other neurotropic infections and enhance our understanding of regulation of neurologic functions.