Injection with Toxoplasma gondii protein affects neuron health and survival

Méndez, Oscar; Machado, Emiliano Flores; Lü, Jing; Koshy, Anita A.

doi:10.7554/elife.67681

Cited by 12 publications

(9 citation statements)

References 69 publications

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“…Both tissues are established sites of T . gondii infection [ 34 , 35 ]; striatum was selected for its role in motor functions and response to rewarding and aversive stimuli [ 36 ], while the hippocampus is involved in memory and learning [ 37 ]. Four biological replicates were performed.…”

Section: Resultsmentioning

confidence: 99%

“…To examine the impact of cocaine and T. gondii infection on gene expression in the mouse brain we performed RNASeq on the striatum and hippocampus from samples collected from all four treatment groups (+/-cocaine and +/-T. gondii). Both tissues are established sites of T. gondii infection [34,35]; striatum was selected for its role in motor functions and response to rewarding and aversive stimuli [36], while the hippocampus is involved in memory and learning [37]. Four biological replicates were performed.…”

Section: Exposure To Cocaine and Chronic Infection By T Gondii Result...mentioning

confidence: 99%

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Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

et al. 2022

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During chronic infection, the single celled parasite, Toxoplasma gondii, can migrate to the brain where it has been associated with altered dopamine function and the capacity to modulate host behavior, increasing risk of neurocognitive disorders. Here we explore alterations in dopamine-related behavior in a new mouse model based on stimulant (cocaine)-induced hyperactivity. In combination with cocaine, infection resulted in heightened sensorimotor deficits and impairment in prepulse inhibition response, which are commonly disrupted in neuropsychiatric conditions. To identify molecular pathways in the brain affected by chronic T. gondii infection, we investigated patterns of gene expression. As expected, infection was associated with an enrichment of genes associated with general immune response pathways, that otherwise limits statistical power to identify more informative pathways. To overcome this limitation and focus on pathways of neurological relevance, we developed a novel context enrichment approach that relies on a customized ontology. Applying this approach, we identified genes that exhibited unexpected patterns of expression arising from the combination of cocaine exposure and infection. These include sets of genes which exhibited dampened response to cocaine in infected mice, suggesting a possible mechanism for some observed behaviors and a neuroprotective effect that may be advantageous to parasite persistence. This model offers a powerful new approach to dissect the molecular pathways by which T. gondii infection contributes to neurocognitive disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Exposure To Cocaine and Chronic Infection By T Gondii Result...mentioning

confidence: 99%

Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

et al. 2022

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“…In T. gondii infection, however, we find that GABAergic perisomatic synapse loss is not a result of temporary displacement, but rather is a process where presynaptic nerve terminals are removed by phagocytosis. If widespread perisomatic synapse loss continues throughout the course of the infection, it may contribute to neuronal death seen in later stages of chronic T. gondii infection (Cabral et al, 2016, Mendez et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Microglia, however, are not the only ones that preferentially interact with excitatory neurons. Recent studies assessing neurons that are injected with T. gondii proteins (but do not contain the parasite itself) shows the parasite, like microglia, also has preference for targeting excitatory neurons (Koshy et al, 2012, Mendez et al, 2021). Thus, excitatory cells could be secreting signaling molecules such as neurotrophins and neuropeptides that attract both microglia and parasites to these cells.…”

Section: Discussionmentioning

confidence: 99%

Complement-dependent loss of inhibitory synapses on pyramidal neurons followingToxoplasma gondiiinfection

Carrillo

Crawley

et al. 2022

Preprint

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The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm-blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, non-human primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. We previously demonstrated that T. gondii infection triggers the loss of perisomatic inhibitory synapses, an important source of inhibition on excitatory pyramidal cells, and a type of synapse that is disrupted in neurological and neuropsychiatric disorders. Similar to other instances of inflammation and neurodegeneration, we showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. However, in the case of T. gondii-induced synapse loss, phagocytic cells target and ensheath the cell bodies of telencephalic neurons. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons. In contrast, inhibitory cortical interneuron subtypes are not extensively ensheathed by phagocytic cells following infection. Moreover, we show that infection induces expression of complement C3 protein by these excitatory neurons and that C3 is required for the loss of perisomatic inhibitory synapses, albeit not through activation of the classical complement pathway. Together, these findings provide evidence that T. gondii infection induces changes in excitatory pyramidal neurons that trigger selective removal of inhibitory perisomatic synapses in the infected neocortex and provide a novel role for complement in remodeling of inhibitory circuits in the infected brain.

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“…During chronic infection, despite cyst-containing neurons and brain inflammation caused by the recruitment of peripheral immune cells, Toxoplasma causes few clinical symptoms in the immunocompetent host. However, underlying changes in neurochemistry and significant changes in the health of neurons [6, 7] suggest a constant need to balance inflammation and protect against neuropathology. Recent work in our lab to determine Toxoplasma-induced changes in immunological and neurological transcripts in the brain [8] supports these neurological changes but also reveals potential neuroprotective pathways that remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronicToxoplasma gondiiinfection

Bergersen

Kavvathas

David

et al. 2022

Preprint

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Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons of the brain that can have devastating consequences in the immunocompromised. However, despite the establishment of a chronic inflammatory state and infection-induced neurological changes, there are limited signs of clinical neuropathology resulting in an asymptomatic infection in the immunocompetent. This suggests the work of neuroprotective mechanisms to prevent clinical manifestations of disease. However, such sources of neuroprotection during infection remain largely unknown. This study identifies a population of neutrophils chronically present in the brain during Toxoplasma infection that express the neuroprotective molecules NRG-1, ErbB4, and MSR1. Further phenotyping of this population via flow cytometry and singe-cell RNA sequencing reveals two distinct subsets of neutrophils based on age that display functional heterogeneity. This includes cells transcriptionally prepared to function both as anti-parasitic effector cells and in a more alternative protective manner. Chronic depletion of neutrophils results in increased parasite burden and infection-induced vascular pathology. Lack of neutrophils during chronic infection also deleteriously affects neuronal regeneration and repair mechanisms. In conclusion, this work identifies and demonstrates a functionally diverse chronic neutrophil population that plays a dynamic role in controlling infection outcome in the CNS by balancing classical responses with neuroprotective functions.

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Injection with Toxoplasma gondii protein affects neuron health and survival

Cited by 12 publications

References 69 publications

Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Complement-dependent loss of inhibitory synapses on pyramidal neurons followingToxoplasma gondiiinfection

Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronicToxoplasma gondiiinfection

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