Spontaneous T. gondii neuronal encystment induces structural neuritic network impairment associated with changes of tyrosine hydroxilase expression

Barbosa, Joana Lobato; Béla, Samantha Ribeiro; Ricci, Mayra Fernanda; Noviello, Maria de Lourdes Meirelles; Cartelle, Christiane Teixeira; Pinheiro, Breno Veloso; Vitor, Ricardo Wagner de Almeida; Arantes, Rosa Maria Esteves

doi:10.1016/j.neulet.2019.134721

Cited by 7 publications

(12 citation statements)

References 30 publications

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“…Other groups have previously utilized neuroblastoma cell lines to investigate the impact of T. gondii infection, where transfection of human neuroblastoma SH-SY5Y cells with ROP16 effector protein led to apoptosis and cell cycle arrest (Chang et al, 2015), which also resulted in the remodeling of host cell transcriptomic networks, including those related to nervous system development, apoptosis and transcriptional regulation (Fan et al, 2016). Our results demonstrating reduced neuritogenesis are also in accordance to what was recently shown in infected cultures of superior cervical ganglion cells, in which neurite networks were decreased in cultures infected with a highly virulent strain of T. gondii (TgCTBr9, genotype #11) from 48 to 192 hpi (Barbosa et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

Infection of mouse neural progenitor cells by Toxoplasma gondii affects in vitro proliferation, differentiation and migration

Pires

Barbosa

Santiago

et al. 2021

Preprint

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Congenital toxoplasmosis constitutes a major cause of pre- and post-natal complications. Fetal infection with Toxoplasma gondii influences development and can lead to microcephaly, encephalitis, and neurological abnormalities. Few studies have attempted to explain the impact of T. gondii infection on the physiology of mature nerve cells, and no systematic study concerning the effect of infection of neural progenitor cells by T. gondii in the biology of these progenitors is available. We infected cortical intermediate progenitor cell cultivated as neurospheres obtained from E16.5 Swiss Webster mice with T. gondii (Me49 strain) tachyzoites to mimic the developing mouse cerebral cortex in vitro. Infection decreased cell proliferation as detected by Ki67 staining at 48 and 72 hours post infection (hpi) in floating neurospheres, resulting in reduced cellularity at 96 hpi. Neurogenic and gliogenic potential, assessed in plated neurospheres, was shown to be impaired in infected cultures, as indicated by neurofilament heavy chain (NF-200) and GFAP staining, respectively. To further investigate the impact of infection on neuronal differentiation, Neuro2a neuroblasts were infected and after 24 hpi, neurogenic differentiation was induced with serum withdrawal. We confirmed that infection induces a decrease in neuroblast-neuron differentiation rates in cells stained for NF-200, with reduced neuritogenesis. Migration rates were analyzed in plated neurospheres. At 120 h after plating, infected cultures exhibited decreased overall migration rates and altered the radial migration of nestin-, GFAP- and NF-200-positive cells. These findings indicate that T. gondii infection of neural progenitor cells may lead to reduced neuro/gliogenesis due to an imbalance in cell proliferation alongside an altered migratory profile. If translated to the in vivo situation, these data could explain, in part, the cortical malformations observed in congenitally infected individuals.

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Section: Discussionsupporting

confidence: 92%

Infection of mouse neural progenitor cells by Toxoplasma gondii affects in vitro proliferation, differentiation and migration

Pires

Barbosa

Santiago

et al. 2021

Preprint

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“…We have not observed a predilection of T gondii infection for any particular cell type, concurring with in vitro studies using rodent and human cells that show cyst formation in both neurons and astrocytes (57,58). It is known that cysts in neuronal processes usually result in neurite and synapse loss (52,59). This is in agreement with our data showing that T. gondii infection reduced the synaptophysin mRNA levels compared to non-infected BrainSpheres, which can be interpreted as a reduction in synapse density.…”

Section: Discussionsupporting

confidence: 89%

“…Several works investigated T. gondii infection effects on dopamine levels, with many describing an increase in its levels. An in vitro study reported the reduction of TH protein levels in the presence of T. gondii without alteration of dopamine levels (52). Other authors did not observe changes in TH mRNA and protein levels, but instead reported increases in dopamine synthesis in PC12 cells (35).…”

Section: Discussionmentioning

confidence: 99%

“…Conversion to cyst forms was observed and the cystic wall of bradyzoites was confirmed by labelling with DBA lectin(47) and structural markers such as amylopectin granules and (51) deposition of a dense granular material under PV membrane. Cystogenesis is an important event related to the presence and permanence of T. gondii in the CNS, process mostly studied in rodents and 2D in vitro models(23,52,53).In BrainSpheres, we observed that T. gondii infection causes a significant reduction in neural cells viability. A significant effect of infection was the reduction in size of the spheroids (~42%), which correlated with the augmented neural cell death.…”

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confidence: 89%

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Morphological and biochemical repercussions ofToxoplasma gondiiinfection in a 3D human brain neurospheres model

Leite

Portes

Pereira

et al. 2020

Preprint

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BackgroundToxoplasmosis is caused by the parasite Toxoplasma gondii that can infect the central nervous system (CNS), promoting neuroinflammation, neuronal loss, neurotransmitter imbalance and behavioral alterations. T. gondii infection is also related to neuropsychiatric disorders such as schizophrenia. The pathogenicity and inflammatory response in rodents are different to the case of humans, compromising the correlation between the behavioral alterations and physiological modifications observed in the disease. In the present work we used BrainSpheres, a 3D CNS model derived from human pluripotent stem cells (iPSC), to investigate the morphological and biochemical repercussions of T. gondii infection in human neural cells.MethodsWe evaluated T. gondii ME49 strain proliferation and cyst formation in both 2D cultured human neural cells and BrainSpheres. Aspects of cell morphology, ultrastructure, viability, gene expression of neural phenotype markers, as well as secretion of inflammatory mediators were evaluated for 2 and 4 weeks post infection in BrainSpheres.ResultsT. gondii can infect BrainSpheres, proliferating and inducing cysts formation, neural cell death, alteration in neural gene expression and triggering the release of several inflammatory mediator.ConclusionsBrainSpheres reproduce many aspects of T. gondii infection in human CNS, constituting a useful model to study the neurotoxicity and neuroinflammation mediated by the parasite. In addition, BrainSpheres can be an important tool for better understanding the possible correlation between psychiatric disorders and human CNS infection with T. gondii

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“…Changes in neurochemistry in the infected brain have previously been reported including alterations in the excitatory and inhibitory neurotransmitters (Xiao et al, 2013;Brooks et al, 2015;David et al, 2016;Barbosa et al, 2020) that suggest that even in the absence of clinical pathology, there are underlying changes in neuronal structure and connectivity that would be described as pathological. To determine the full extent of genetic changes related to neuropathology, we analyzed a group of genes with known roles in transmitter function, neural connectivity and function, and neural maintenance and repair via GSA and pathway analyses.…”

Section: Kinetic Analysis Reveals Progressive Neuropathological Changmentioning

confidence: 98%

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

Bergersen

Barnes

Worth

et al. 2021

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii is a resilient parasite that infects a multitude of warm-blooded hosts and results in a lifelong chronic infection requiring continuous responses by the host. Chronic infection is characterized by a balanced immune response and neuropathology that are driven by changes in gene expression. Previous research pertaining to these processes has been conducted in various mouse models, and much knowledge of infection-induced gene expression changes has been acquired through the use of high throughput sequencing techniques in different mouse strains and post-mortem human studies. However, lack of infection time course data poses a prominent missing link in the understanding of chronic infection, and there is still much that is unknown regarding changes in genes specifically relating to neuropathology and resulting repair mechanisms as infection progresses throughout the different stages of chronicity. In this paper, we present a targeted approach to gene expression analysis during T. gondii infection through the use of NanoString nCounter gene expression assays. Wild type C57BL/6 and BALB/c background mice were infected, and transcriptional changes in the brain were evaluated at 14, 28, and 56 days post infection. Results demonstrate a dramatic shift in both previously demonstrated and novel gene expression relating to neuropathology and resolution in C57BL/6 mice. In addition, comparison between BALB/c and C57BL/6 mice demonstrate initial differences in gene expression that evolve over the course of infection and indicate decreased neuropathology and enhanced repair in BALB/c mice. In conclusion, these studies provide a targeted approach to gene expression analysis in the brain during infection and provide elaboration on previously identified transcriptional changes and also offer insights into further understanding the complexities of chronic T. gondii infection.

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Spontaneous T. gondii neuronal encystment induces structural neuritic network impairment associated with changes of tyrosine hydroxilase expression

Cited by 7 publications

References 30 publications

Infection of mouse neural progenitor cells by Toxoplasma gondii affects in vitro proliferation, differentiation and migration

Infection of mouse neural progenitor cells by Toxoplasma gondii affects in vitro proliferation, differentiation and migration

Morphological and biochemical repercussions ofToxoplasma gondiiinfection in a 3D human brain neurospheres model

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

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