GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii

Fuks, Jonas M.; Arrighi, Romanico B. G.; Weidner, Jessica M.; Mendu, Suresh K.; Jin, Zhe; Wallin, Robert P. A.; Réthi, Bence; Birnir, Bryndis; Barragán, Antonio

doi:10.1371/journal.ppat.1003051

Cited by 148 publications

(288 citation statements)

References 69 publications

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“…Several studies have demonstrated that immune cells infected with T. gondii become hypermotile (27)(28)(29)(30)(31)(32)(33)(34)41), an effect that has been proposed to facilitate the dissemination of the intracellular parasite in the infected host. In the present study, we have demonstrated that the hypermotility of T. gondii-infected human monocytes is linked to a dysregulation in integrin-dependent cell adhesion through defects in FAK-regulated focal adhesions.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Cook¹,

Ueno²,

Lodoen

2018

Journal of Biological Chemistry

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The motility of blood monocytes is orchestrated by the activity of cell surface integrins, which translate extracellular signals into cytoskeletal changes to mediate adhesion and migration. Toxoplasma gondii is an intracellular parasite that infects migratory cells and enhances their motility, but the mechanisms underlying T. gondii-induced hypermotility are incompletely understood. We have investigated the molecular basis for the hypermotility of primary human peripheral blood monocytes and THP-1 cells infected with T. gondii. Compared to uninfected monocytes, T. gondii infection of monocytes reduced cell spreading and the number of activated β1 integrin clusters in contact with fibronectin during settling, an effect not observed in monocytes treated with LPS or E. coli. Furthermore, T. gondii infection disrupted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 (Y397) and Y925 and of the related protein proline-rich tyrosine kinase (Pyk2) at Y402. The localization of paxillin, FAK, and vinculin to focal adhesions and the colocalization of these proteins with activated β1 integrins were also impaired in T. gondiiinfected monocytes. Using time-lapse confocal microscopy of THP-1 cells expressing eGFP-FAK during settling on fibronectin, we found that T. gondii-induced monocyte hypermotility was characterized by a reduced number of eGFP-FAKcontaining clusters over time compared to uninfected cells. This study demonstrates an integrin conformation-independent regulation of the β1 integrin adhesion pathway, providing further insight into the molecular mechanism of T. gondiiinduced monocyte hypermotility.

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Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Cook¹,

Ueno²,

Lodoen

2018

Journal of Biological Chemistry

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“…While the exact mechanism by which latent toxoplasmosis affects behaviour is unclear, T. gondii can exist intracellularly in the brain throughout the life of the host (Carruthers and Suzuki 2007), potentially modifying neural structure or function (Berenreiterová et al 2011, Prandovszky et al 2011, Fuks et al 2012. Indeed, T. gondii appears to alter dopamine metabolism (Parlog et al 2015), with the potential to substantially increase dopamine concentration in the brain (Berenreiterová et al 2011).…”

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confidence: 99%

No association between current depression and latent toxoplasmosis in adults

et al. 2016

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Changes in behaviour and cognition have been associated with latent infection from the apicomplexan protozoan Toxoplasma gondii (Nicolle et Manceaux, 1908) in both animal and human studies. Further, neuropsychiatric disorders such as schizophrenia have also been associated with latent toxoplasmosis. Previously, we found no association between T. gondii immunoglobulin G antibody (IgG) seropositivity and depression in human adults between the ages of 20 and 39 years (n = 1 846) in a sample representative of the United States collected by the Centers for Disease Control as part of a National Health and Nutrition Examination Survey (NHANES) from three datasets collected between 1999-2004. In the present study, we used NHANES data collected between 2009 and 2012 that included subjects aged 20 to 80 years (n = 5 487) and used the Patient Health Questionnaire 9 (PHQ-9) to assess depression with the overall aim of testing the stability of the results of the prior study. In the current study, the seroprevalence of T. gondii was 13%. The percentage of subjects reporting clinical levels of depression assessed with the PHQ-9 was 8%. As before, we found no association between T. gondii IgG seroprevalence and depression (OR = 1.01, 95% CI = 0.81-1.25; p = 0.944) while controlling for sex, educational attainment, race-ethnicity, age, poverty-to-income ratio and cigarette smoking. We also found no positive associations between anti-T. gondii antibody titre and depression (OR = 1.00, 95% CI = 0.96-1.06; p = 0.868). Moreover, we found no association between T. gondii seroprevalence or antibody titre and suicidal ideation (seroprevalence: OR = 1.22, 95% CI = .85-1.75; p = 0.277, titre: OR = 1.05, 95% CI = 0.98-1.14; p = 0.177). Defining depression to also include subjects currently taking antidepressant medication even with non-elevated questionnaires did not find evidence of a positive association between latent toxoplasmosis and depression. In the present study, neither T. gondii seroprevalence nor anti-T. gondii antibody titre was positively associated with depression or suicidal ideation among subjects aged 20 to 80 years.

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“…Although dendritic cells are considered guardians of the immune system, they can also, paradoxically, mediate in the spread of the parasite. This mechanism is produced by the induction in these cells of the GAD enzyme and therefore of GABA production and secretion, which in turn activate GABA receptors expressed by these same cells, stimulating their motility [137]. In experimental mouse models, inhibition of the GABAergic pathway by blockade of GABAA receptors or inhibition of the GAD enzyme markedly reduced the hypermotility and spread of T. gondii-infected dendritic cells and therefore of the parasite itself [137,138].…”

Section: The Importance Of Dopamine and Other Neurotransmittersmentioning

confidence: 99%

“…This mechanism is produced by the induction in these cells of the GAD enzyme and therefore of GABA production and secretion, which in turn activate GABA receptors expressed by these same cells, stimulating their motility [137]. In experimental mouse models, inhibition of the GABAergic pathway by blockade of GABAA receptors or inhibition of the GAD enzyme markedly reduced the hypermotility and spread of T. gondii-infected dendritic cells and therefore of the parasite itself [137,138]. Finally, it has also been reported that brain infection by T. gondii can interfere with the GABAergic system by inducing changes in the distribution of the GAD67 enzyme, although this event has been related more to possible neurological complications of toxoplasmic encephalitis, such as seizures [139], than to possible complications of latent toxoplasmosis, such as schizophrenia.…”

Section: The Importance Of Dopamine and Other Neurotransmittersmentioning

confidence: 99%

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

Sorlózano-Puerto¹,

Gutiérrez‐Fernández²

2016

Schizophrenia Treatment - The New Facets

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Over recent years, it has been proposed that some diseases of unknown origin, such as schizophrenia, may be caused by persistent chronic infections coupled with a genetic component and may be perpetuated by the immune system. This hypothesis is supported by epidemiological and biological evidence on the exposure of schizophrenics to infectious diseases during prenatal or postnatal periods, including Toxoplasma gondii, chlamydia, human herpes virus, human endogenous retroviruses, parvovirus B19, mumps, and flu viruses. This growing list of microbes will undoubtedly continue to increase in the future. Linking infection to schizophrenia is a complex challenge that requires further experimental and epidemiological research. T. gondii is the infectious agent that has most frequently been related to neuropsychiatric disorders, including schizophrenia, and it is considered to represent a highly useful model to analyze the influence of a microorganism on human behavior and the development of psychiatric disease. It may also help to detect patient subpopulations susceptible to treatment with specific antimicrobials by improving definition of the differential phenotype of the disease, and it offers the possibility of a preventive approach.

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GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii

Cited by 148 publications

References 69 publications

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

No association between current depression and latent toxoplasmosis in adults

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

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