Downregulation of the central noradrenergic system by Toxoplasma gondii infection

Abstract

26The parasitic protozoan Toxoplasma gondii becomes encysted in brain and muscle tissue 27 during chronic infection, a stage that was previously thought to be dormant but has been 28 found to be active and associated with physiological effects in the host. Dysregulation of 29 catecholamines in the CNS has previously been observed in chronically-infected animals. In 30 the study described here, the noradrenergic system was suppressed with decreased levels of 31 norepinephrine in brains of infected animals and in infected neuronal cells in vitro. 32 Expression of dopamine β-hydroxylase (DBH), essential for synthesis of norepinephrine 33 from dopamine, was the most differentially-expressed gene in infections in vitro and was 34 down-regulated in infected brain tissue, particularly in the prefrontal cortex and dorsal locus 35 coeruleus/pons region. The down-regulated DBH expression in infected rat 36 catecholaminergic and human neuronal cells corresponded with decreased norepinephrine 37 and increased dopamine. As the DBH suppression was observed in vitro, this effect is not 38 caused by neuroinflammation. Silencing of DBH expression was specific for T. gondii infection 39 and was not observed with CMV infection. The noradrenergic-linked behaviors of sociability 40 and arousal were altered in chronically-infected animals, with a high correlation between 41 DBH expression and infection intensity. These findings together provide a plausible 42 mechanism to explain prior discrepancies in changes to CNS neurotransmitters levels with 43 infection. The suppression of norepinephrine synthesis observed here may, in part, explain 44 behavioural effects of infection, associations with mental illness, and neurological 45 3 consequences of infection such as the loss of coordination and motor impairments associated 46 with human toxoplasmosis. 47 48T. gondii infects warm-blooded animals and is characterised by a transient acute infection 49 wherein vegetative tachyzoite forms rapidly replicate in tissues followed by a persistent 50 chronic infection. Chronic stages of infection can persist for years and potentially the lifetime 51 of the host with the bradyzoite-stage parasites encysted in cells within immunoprivileged 52 tissues, including muscle, eyes, and brain. Several reports have published host behavioral 53 changes with infection. A selective loss of aversion to feline urine and increased motor 54 activity has been observed in rodents, specifically manipulating behavior that will enhance 55 the probability of parasite transmission (1, 2). 56Toxoplasmosis can be a severe disease in immunocompromised individuals and in utero. 57Infection can cause retinochoroiditis and congenital hydrocephalus and cerebral 58 calcifications. T. gondii was recently ranked the second most important food-borne parasite 59 in Europe and is classified as a Neglected Parasitic Infection (CDC, Atlanta) (3). It has also 60 been linked by epidemiological studies to cognitive impairment and major mental illnesses. 61Severe cases are ass...

Infection-Induced Extracellular Vesicles Evoke Neuronal Transcriptional and Epigenetic Changes

“…Future experiments will further investigate this novel induced lncRNA. hence, the widespread DBH down-regulation provides an explanation for changes in noradrenergic-linked behaviours in chronically-infected mice (13,52). We propose a model of T. gondii inducing host-encoded lncRNAs that are packaged and released from host neuronal cells during chronic infection to modulate the host environment; extending studies that found T. gondii-infected fibroblasts and macrophages can induce host lncRNAs (53).…”

“…(4)(5)(6). The changes are associated with neurotransmitter modifications and neuroinflammation although the mechanisms responsible are poorly understood (7)(8)(9)(10)(11)(12)(13). Seropositivity in humans ranges from 10-90% in different parts of the world with >40m people in the USA carrying the parasite (DPDx, Centers for Disease Control, USA).…”

Toxoplasma Immunomodulation Related to Neuropsychiatric Diseases

“…This explains the observation of high-concentration tissue cysts in the amygdala and nucleus accumbens, containing dopamine in limbic regions of the brain known to be an important control of motivation, pleasure, dependence, reward, and fear [47]. Other effects are more intriguing; Alteration of the neurotransmitter involves the production of homologous proteins to aromatic amino acid TH and dopamine (DOPA) 2 receptor (D2R) compounds with an increase in DOPA synthesis, tryptophan (TRP) degradation and the decrease in serotonin synthesis [56,65].…”

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

“…In addition to an inflammatory response, T. gondii infection causes several neurochemical changes including glutamate and dopamine dysregulation [189,190]. During chronic infection with T. gondii, the astrocytic glutamate transporter GLT-1 is reportedly reduced in the forebrain over time, leading to increases in extracellular glutamate and excitotoxicity [189].…”