Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system.
Ontology highlight
ABSTRACT:
SUBMITTER: Mendez OA
PROVIDER: S-EPMC5519211 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:An important function of the blood-brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood-brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system.
| S-EPMC4966557 | biostudies-literature
Project description:UNLABELLED:During infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling. IMPORTANCE:Infections of the central nervous system can cause seizures. While inflammation in the brain has been proposed to initiate the onset of the seizures, relatively little is known about how inflammation impacts the structure and function of the neurons. Here we used a parasite called Toxoplasma gondii that infects the brain and showed that seizures arise due to a defect in signaling of GABA, which is the neurotransmitter primarily responsible for preventing the onset of seizures.
| S-EPMC4626855 | biostudies-literature
Project description:Toxoplasma gondii is an obligate intracellular protozoan pathogen that traffics to the central nervous system (CNS) following invasion of its host. In the CNS, T. gondii undergoes transformation from a rapidly dividing tachyzoite to a long-lived, slow-dividing bradyzoite contained within cysts. The role of extracellular adenosine in T. gondii pathogenesis has not been previously investigated. T. gondii uses host purines such as adenosine for its energy needs, as it is unable to make its own. Here, we show that CD73(-/-) mice, which lack the ability to generate extracellular adenosine, are protected from T. gondii chronic infection, with significantly fewer cysts and reduced susceptibility to reactivation of infection in the CNS independent of host effector function. Parasite dissemination to the brain was unimpaired in CD73(-/-) hosts, suggesting that the reduced cyst number is due to impaired parasite differentiation in the CNS. Confirming this, T. gondii tachyzoites formed fewer cysts following alkaline pH stress in astrocytes isolated from CD73(-/-) mice compared with wild type, and in fibroblasts treated with a CD73 inhibitor. Cyst formation was rescued in CD73(-/-) astrocytes supplemented with adenosine, but not with adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine. Furthermore, mice lacking adenosine receptors had no defect in cyst formation. Based on these findings, we conclude that CD73 expression promotes Toxoplasma bradyzoite differentiation and cyst formation by a mechanism dependent on the generation of adenosine, but independent of adenosine receptor signaling. Overall, these findings suggest that modulators of extracellular adenosine may be used to develop therapies aimed at defending against human toxoplasmosis.
| S-EPMC3479617 | biostudies-literature
Project description:Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro The mechanism responsible for the NE suppression was found to be downregulation of dopamine ?-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.
| S-EPMC6346129 | biostudies-literature
Project description:Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
| S-EPMC5746462 | biostudies-literature
Project description:Ca2+ signaling impacts almost every aspect of cellular life. Ca2+ signals are generated through the opening of ion channels that permit the flow of Ca2+ down an electrochemical gradient. Cytosolic Ca2+ fluctuations can be generated through Ca2+ entry from the extracellular milieu or release from intracellular stores. In Toxoplasma gondii, Ca2+ ions play critical roles in several essential functions for the parasite, like invasion of host cells, motility, and egress. Plasma membrane Ca2+ entry in T. gondii was previously shown to be activated by cytosolic calcium and inhibited by the voltage-operated Ca2+ channel blocker nifedipine. However, Ca2+ entry in T. gondii did not show the classical characteristics of store regulation. In this work, we characterized the mechanism by which cytosolic Ca2+ regulates plasma membrane Ca2+ entry in extracellular T. gondii tachyzoites loaded with the Ca2+ indicator Fura-2. We compared the inhibition by nifedipine with the effect of the broad spectrum TRP channel inhibitor, anthranilic acid or ACA, and we find that both inhibitors act on different Ca2+ entry activities. We demonstrate, using pharmacological and genetic tools, that an intracellular signaling pathway engaging cyclic GMP, protein kinase G, Ca2+, and the phosphatidyl inositol phospholipase C affects Ca2+ entry and we present a model for crosstalk between cyclic GMP and cytosolic Ca2+ for the activation of T. gondii's lytic cycle traits.
| S-EPMC10959671 | biostudies-literature
Project description:The brown ghost knifefish (Apteronotus leptorhynchus) is a weakly electric teleost fish of particular interest as a model organism for a variety of research areas in neuroscience, including neurophysiology, neuroethology, and neurobiology. This versatile model system has been more recently used in the study of central nervous system development and regeneration during adulthood, as well as in the study of vertebrate aging and senescence. Despite substantial scientific interest in this species, no genomic resources are currently available. After evaluating several trimming and transcript reconstruction strategies, de novo assembly using Trinity uncovered at least 11,847 unique components (“genes”) containing full or near-full length protein sequences based on alignment to a reference set of known Actinopterygii protein sequences, with as many as 42,459 components containing at least a partial protein-coding sequence, providing broad coverage of the proteome. Shotgun proteomics confirmed translation of open reading frames from over 2,000 transcripts, including alternative splice variants. Assignment of tandem mass spectra obtained was shown to be greatly improved with the assembly compared with using databases of sequences from closely related organisms.
2015-07-16 | PXD001285 | Pride
Project description:Purpose of reviewCentral nervous system (CNS) tuberculosis is the most devastating form of tuberculosis (TB), with mortality and or neurological sequelae in over half of individuals. We reviewed original research and systematic reviews published since 1 January 2019 for new developments in CNS TB pathophysiology, diagnosis, management and prognosis.Recent findingsInsight in the pathophysiology is increasing steadily since the landmark studies in 1933, focussing on granuloma type classification, the relevance of the M. tuberculosis bacterial burden and the wide range of immunological responses. Although Xpert/RIF has been recommended by the WHO for extrapulmonary TB diagnosis, culture is still needed to increase the sensitivity of TB meningitis diagnosis. Sequential MRIs can improve understanding of neurological deficits at baseline and during treatment. Pharmacokinetic/pharmacodynamic modelling suggests that higher doses of rifampicin and isoniazid in TB meningitis could improve survival.SummaryRecent studies in the field of CNS-TB have largely focussed on TB meningitis. The outcome may improve by optimizing treatment dosing. This needs to be confirmed in clinical trials. Due to the important role of inflammation, these trials should be used as the platform to study the inflammatory and metabolomic responses. This could improve understanding of the biology of this disease and improve patient outlook by enabling individualised host-directed therapy.
| S-EPMC8283909 | biostudies-literature
Project description:Encephalitis is a hallmark of Nipah virus (NiV) infection in humans. The exact route of entry of NiV into the central nervous system (CNS) is unknown. Here, we performed a spatio-temporal analysis of NiV entry into the CNS of hamsters. NiV initially predominantly targeted the olfactory epithelium in the nasal turbinates. From there, NiV infected neurons were visible extending through the cribriform plate into the olfactory bulb, providing direct evidence of rapid CNS entry. Subsequently, NiV disseminated to the olfactory tubercle and throughout the ventral cortex. Transmission electron microscopy on brain tissue showed extravasation of plasma cells, neuronal degeneration and nucleocapsid inclusions in affected tissue and axons, providing further evidence for axonal transport of NiV. NiV entry into the CNS coincided with the occurrence of respiratory disease, suggesting that the initial entry of NiV into the CNS occurs simultaneously with, rather than as a result of, systemic virus replication.
| S-EPMC3471094 | biostudies-literature
Project description:The balance between controlling infection and limiting inflammation is particularly precarious in the brain because of its unique vulnerability to the toxic effects of inflammation. Astrocytes have been implicated as key regulators of neuroinflammation in CNS infections, including infection with Toxoplasma gondii, a protozoan parasite that naturally establishes a chronic CNS infection in mice and humans. In CNS toxoplasmosis, astrocytes are critical to controlling parasite growth. They secrete proinflammatory cytokines and physically encircle parasites. However, the molecular mechanisms used by astrocytes to limit neuroinflammation during toxoplasmic encephalitis have not yet been identified. TGF-β signaling in astrocytes is of particular interest because TGF-β is universally upregulated during CNS infection and serves master regulatory and primarily anti-inflammatory functions. We report in this study that TGF-β signaling is activated in astrocytes during toxoplasmic encephalitis and that inhibition of astrocytic TGF-β signaling increases immune cell infiltration, uncouples proinflammatory cytokine and chemokine production from CNS parasite burden, and increases neuronal injury. Remarkably, we show that the effects of inhibiting astrocytic TGF-β signaling are independent of parasite burden and the ability of GFAP(+) astrocytes to physically encircle parasites.
| S-EPMC4075480 | biostudies-literature