Toxoplasma gondii infection impairs radial glia differentiation and its potential to modulate brain microvascular endothelial cell function in the cerebral cortex

Marcos, Anne Caroline; Siqueira, Michele; Alvarez-Rosa, Liandra; Cascabulho, Cynthia Machado; Waghabi, Mariana Caldas; Barbosa, Helene Santos; Adesse, Daniel; Stipursky, Joice

doi:10.1016/j.mvr.2020.104024

Cited by 13 publications

(12 citation statements)

References 59 publications

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“…Finally, astrogliogenesis, as revealed by GFAP immunostaining was significantly reduced in infected cultures. This contrasts with what we recently described in radial glia culture infection, in which GFAP+ cells remained unaltered (Marcos et al, 2020). Contrasting results regarding neuronal and astrocytic differentiation in radial glia and intermediate progenitors due to T. gondii infection may, in fact, reinforce the differences in clinical outcomes when vertical transmission occurs during different gestational periods.…”

Section: Discussioncontrasting

confidence: 99%

“…This effect was inhibited in T. gondii infected cultures. Impaired neurogenic potential (as estimated by TUJ1+ cells) was previously demonstrated by our group in radial glia cell cultures infected with Me49 tachyzoites (Marcos et al, 2020). This effect was also observed when C17.2 neural stem cell line cells were treated with soluble factors released from T. gondii (Gan et al, 2016), in a process mediated by the Wnt/β-catenin signaling pathway.…”

Section: Discussionsupporting

confidence: 58%

“…In vitro stage conversion has been shown to occur in neural cell cultures (Lüder et al, 1999) and in our neurosphere cultures, bradyzoite-specific BAG-1 mRNA have been detected at 96 hpi by RT-PCR (Adesse, D., personal observation). Our group recently described that radial glial cell infection with T. gondii tachyzoites (Me49 strain, the same utilized herein), led to proliferation reduction with no apoptosis induction (Marcos et al, 2020) of these early neural stem cells. Therefore, reduced proliferation in infected dishes could contribute to reduced neurogenesis in infected animals.…”

Section: Discussionmentioning

confidence: 90%

“…Contrasting results regarding neuronal and astrocytic differentiation in radial glia and intermediate progenitors due to T. gondii infection may, in fact, reinforce the differences in clinical outcomes when vertical transmission occurs during different gestational periods. Moreover, our group has shown, using two independent systems, that T. gondii decreases the secretion of transforming growth factor beta 1 (TGF-β1), in both radial glia (Marcos et al, 2020) and skeletal muscle cells (Vieira et al, 2019). TGF-β1 is a pleiotropic cytokine involved in organogenesis and pathogenic events in vertebrates (reviewed by Massagué, 1998).…”

Section: Discussionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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

Pires

Barbosa

Santiago

et al. 2021

Preprint

Self Cite

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“…T. gondii infection was found to deregulate radial glia (RG) cell proliferation, differentiation potential, and decrease TGF-β1 levels. T. gondii infection of RG cells resulted in impairment of endothelial cell barrier functions through disorganization of cell junction-associated ZO-1 and reduced trans-endothelial electrical resistance (TEER) [ 12 ]. Infection of primary human umbilical vein endothelial cells by T. gondii caused alteration of the morphology, barrier permeability, and transcriptional profile of the infected cells.…”

Section: Introductionmentioning

confidence: 99%

Structural, Functional, and Metabolic Alterations in Human Cerebrovascular Endothelial Cells during Toxoplasma gondii Infection and Amelioration by Verapamil In Vitro

et al. 2020

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Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with and crosses the blood–brain barrier (BBB). The present study revealed structural and functional changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. T. gondii proliferated within the BMECs and disrupted the integrity of the cerebrovascular barrier through diminishing the cellular viability, disruption of the intercellular junctions and increasing permeability of the BMEC monolayer, as well as altering lipid homeostasis. Proton nuclear magnetic resonance (1H NMR)-based metabolomics combined with multivariate data analysis revealed profiles that can be attributed to infection and variations in the amounts of certain metabolites (e.g., amino acids, fatty acids) in the extracts of infected compared to control cells. Notably, treatment with the Ca2+ channel blocker verapamil rescued BMEC barrier integrity and restricted intracellular replication of the tachyzoites regardless of the time of treatment application (i.e., prior to infection, early- and late-infection). This study provides new insights into the structural and functional changes that accompany T. gondii infection of the BMECs, and sheds light upon the ability of verapamil to inhibit the parasite proliferation and to ameliorate the adverse effects caused by T. gondii infection.

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Infection of Mouse Neural Progenitor Cells by Toxoplasma gondii Reduces Proliferation, Migration, and Neuronal Differentiation in Vitro

Pires¹,

Peixoto-Rodrigues²,

Eloi³

et al. 2023

The American Journal of Pathology

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Toxoplasma gondii infection impairs radial glia differentiation and its potential to modulate brain microvascular endothelial cell function in the cerebral cortex

Cited by 13 publications

References 59 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

Structural, Functional, and Metabolic Alterations in Human Cerebrovascular Endothelial Cells during Toxoplasma gondii Infection and Amelioration by Verapamil In Vitro

Infection of Mouse Neural Progenitor Cells by Toxoplasma gondii Reduces Proliferation, Migration, and Neuronal Differentiation in Vitro

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