Radial Glia cell infection by<i>Toxoplasma gondii</i>disrupts brain microvascular endothelial cell integrity

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

doi:10.1101/378588

Cited by 3 publications

(3 citation statements)

References 83 publications

(117 reference statements)

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“…However, our data indicate that infected C2C12 cells display reduced TGF-β1 secretion. This behavior was also observed by our group after T. gondii infection of neural progenitors (Adesse et al, 2018). Regarding muscle cells, Swierzy et al (2014) previously demonstrated T. gondii infection effects on the TGF-β mRNA expression of myoblasts and myotubes.…”

Section: Discussionsupporting

confidence: 84%

Toxoplasma gondii Impairs Myogenesis in vitro, With Changes in Myogenic Regulatory Factors, Altered Host Cell Proliferation and Secretory Profile

Vieira

Waghabi

Beghini

et al. 2019

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii is the causative agent of toxoplasmosis, a parasitic disease with a wide global prevalence. The parasite forms cysts in skeletal muscle cells and neurons, although no evident association with inflammatory infiltrates has been typically found. We studied the impact of T. gondii infection on the myogenic program of mouse skeletal muscle cells (SkMC). The C2C12 murine myoblast cell line was infected with T. gondii tachyzoites (ME49 strain) for 24 h followed by myogenic differentiation induction. T. gondii infection caused a general decrease in myotube differentiation, fusion and maturation, along with decreased expression of myosin heavy chain. The expression of Myogenic Regulatory Factors Myf5, MyoD, Mrf4 and myogenin was modulated by the infection. Infected cultures presented increased proliferation rates, as assessed by Ki67 immunostaining, whereas neither host cell lysis nor apoptosis were significantly augmented in infected dishes. Cytokine Bead Array indicated that IL-6 and MCP-1 were highly increased in the medium from infected cultures, whereas TGF-β1 was consistently decreased. Inhibition of the IL-6 receptor or supplementation with recombinant TGF-β failed to reverse the deleterious effects caused by the infection. However, conditioned medium from infected cultures inhibited myogenesis in C2C12 cells. Activation of the Wnt/β-catenin pathway was impaired in T. gondii-infected cultures. Our data indicate that T. gondii leads SkMCs to a pro-inflammatory phenotype, leaving cells unresponsive to β-catenin activation, and inhibition of the myogenic differentiation program. Such deregulation may suggest muscle atrophy and molecular mechanisms similar to those involved in myositis observed in human patients.

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Section: Discussionsupporting

confidence: 84%

Toxoplasma gondii Impairs Myogenesis in vitro, With Changes in Myogenic Regulatory Factors, Altered Host Cell Proliferation and Secretory Profile

Vieira

Waghabi

Beghini

et al. 2019

Front. Cell. Infect. Microbiol.

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“…One recent study reported on the prevalence of T. gondii in a series of human autopsy samples, and the authors stated that T. gondii was detected in the neurons and astrocytes in the brains of these toxoplasmosis patients [37], findings consistent with our data. Regarding radial glial cells, one report demonstrated that T. gondii can infect rodent radial glial cells [38]; however, the considerable differences between humans and other species is notable. To date, it is not known whether human radial glial cells are susceptible to T. gondii.…”

Section: Discussionmentioning

confidence: 99%

Modelling Toxoplasma gondii infection in human cerebral organoids

Seo

Han

Lee

et al. 2020

Emerging Microbes & Infections

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Pluripotent stem cell-derived cerebral organoids have the potential to recapitulate the pathophysiology of in vivo human brain tissue, constituting a valuable resource for modelling brain disorders, including infectious diseases. Toxoplasma gondii, an intracellular protozoan parasite, infects most warm-blooded animals, including humans, causing toxoplasmosis. In immunodeficient patients and pregnant women, infection often results in severe central nervous system disease and fetal miscarriage. However, understanding the molecular pathophysiology of the disease has been challenging due to limited in vitro model systems. Here, we developed a new in vitro model system of T. gondii infection using human brain organoids. We observed that tachyzoites can infect human cerebral organoids and are transformed to bradyzoites and replicate in parasitophorous vacuoles to form cysts, indicating that the T. gondii asexual life cycle is efficiently simulated in the brain organoids. Transcriptomic analysis of T. gondii-infected organoids revealed the activation of the type I interferon immune response against infection. In addition, in brain organoids, T. gondii exhibited a changed transcriptome related to protozoan invasion and replication. This study shows cerebral organoids as physiologically relevant in vitro model systems useful for advancing the understanding of T. gondii infections and host interactions.

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“…The endothelium is responsible for keeping vascular tone and controlling oxidative stress by releasing mediators such as nitric oxide (NO), endothelin, and prostacyclin and regulating angiotensin-II activity. Reduction of vascular endothelium in response to appropriate stimuli is the main feature of endothelial dysfunction (8).…”

Section: Introductionmentioning

confidence: 99%

Toxoplasmosis and Risk of Endothelial Dysfunction: Role of Oxidative Stress and Pro-Inflammatory Mediators

Al-Kuraishy

Al-Kuraishi

Al-Windy

et al. 2020

Arch Clin Infect Dis

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Background: Infection with Toxoplasma gondii (T. gondii) leads to activation of T-helper cells (Th-1 and Th-2) which are involved in the synthesis and release of different cytokines which may lead to endothelial dysfunction. Objectives: To evaluate the endothelial function in patients with acute toxoplasmosis. Methods: This case-control study involved 31 patients with toxoplasmosis aged 19 -47 years matched with 20 healthy subjects. Anti-T. gondii antibody (IgG, IgM, IgA) was determined by direct antigen-antibody reaction. Interleukin-6(IL-6), endothelin-1 (ET-1) and human malondialdehyde (MDA) serum levels were measured. Results: IgM, IgG and IgA levels were high in the infected patients compared with controls (P < 0.01). Furthermore, IL-6 serum level was high in the infected patients compared with controls (P < 0.01). In addition, ET-1 level was high in acute toxoplasmosis (7.29 ± 4.59 pg/mL) compared with controls (3.11 ± 1.69 pg/mL) (P < 0.01). In addition, MDA serum level was high (9.34 ± 4.17 nmol/mL) compared with controls (2.87 ± 1.13 nmol/mL), (P < 0.01). In acute toxoplasmosis IgM serum level was significantly correlated with IgG (r = 0.55, P = 0.001), IgA (r = 0.57, P = 0.0008), IL-6 (r = 0.45, P = 0.01), ET-1 (r = 0.51, P = 0.003) and MDA (r = 0.85, P = 0.0001). Conclusions: Acute toxoplasmosis is associated with significant oxidative stress and pro-inflammatory changes which contribute to development of endothelial dysfunction.

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Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Cited by 3 publications

References 83 publications

Toxoplasma gondii Impairs Myogenesis in vitro, With Changes in Myogenic Regulatory Factors, Altered Host Cell Proliferation and Secretory Profile

Toxoplasma gondii Impairs Myogenesis in vitro, With Changes in Myogenic Regulatory Factors, Altered Host Cell Proliferation and Secretory Profile

Modelling Toxoplasma gondii infection in human cerebral organoids

Toxoplasmosis and Risk of Endothelial Dysfunction: Role of Oxidative Stress and Pro-Inflammatory Mediators

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