The Meningococcal ABC-Type l-Glutamate Transporter GltT Is Necessary for the Development of Experimental Meningitis in Mice

ABSTRACT Experimental animal models of bacterial meningitis are useful to study the host-pathogen interactions occurring at the cerebral level and to analyze the pathogenetic mechanisms behind this life-threatening disease. In this study, we have developed a mouse model of meningococcal meningitis based on the intracisternal inoculation of bacteria. Experiments were performed with mouse-passaged serogroup C Neisseria meningitidis. Survival and clinical parameters of infected mice and microbiological and histological analysis of the brain demonstrated the establishment of meningitis with features comparable to those of the disease in humans. When using low bacterial inocula, meningococcal replication in the brain was very efficient, with a 1,000-fold increase of viable counts in 18 h. Meningococci were also found in the blood, spleens, and livers of infected mice, and bacterial loads in different organs were dependent on the infectious dose. As glutamate uptake from the host has been implicated in meningococcal virulence, mice were infected intracisternally with an isogenic strain deficient in the ABC-type l-glutamate transporter GltT. Noticeably, the mutant was attenuated in virulence in mixed infections, indicating that wild-type bacteria outcompeted the GltT-deficient meningococci. The data show that the GltT transporter plays a role in meningitis and concomitant systemic infection, suggesting that meningococci may use l-glutamate as a nutrient source and as a precursor to synthesize the antioxidant glutathione.

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PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation

Communications Biology ◽

10.1038/s42003-020-01435-w ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Hiroki Yasuda ◽

Hikaru Yamamoto ◽

Kenji Hanamura ◽

Mona Mehruba ◽

Toshio Kawamata ◽

...

Keyword(s):

Protein Kinase ◽

Metabotropic Glutamate Receptor ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Critical Role ◽

Glutamate Transporter ◽

Wild Type ◽

Excitatory Amino Acid Transporter ◽

The Brain ◽

Neuronal Glutamate Transporter

AbstractAbnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.

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A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22136974 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6974

Author(s):

Omar Taleb ◽

Mohammed Maammar ◽

Christian Klein ◽

Michel Maitre ◽

Ayikoe Guy Mensah-Nyagan

Keyword(s):

Dopamine Release ◽

Intraperitoneal Administration ◽

Glutamate Transporter ◽

Fold Increase ◽

Xanthurenic Acid ◽

Metabotropic Receptors ◽

Parent Molecule ◽

Dopaminergic Activity ◽

The Brain

Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1–0.4 µM in A9 and A10), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.

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Efficacy of the Endolysin-Based Antibacterial Gel for Treatment of Anaerobic Infection Caused by Fusobacterium necrophorum

Antibiotics ◽

10.3390/antibiotics10101260 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1260

Author(s):

Daria V. Vasina ◽

Nataliia P. Antonova ◽

Aleksei M. Vorobev ◽

Aleksei I. Laishevtsev ◽

Andrei V. Kapustin ◽

...

Keyword(s):

Bacterial Infections ◽

Acute Inflammation ◽

Bacterial Species ◽

Systemic Infection ◽

Fold Increase ◽

Fusobacterium Necrophorum ◽

Abscess Formation ◽

Gram Negative ◽

Gel Treatment ◽

Life Threatening

Abscess formation is a common complication of severe life-threatening infections caused by obligate anaerobes. Fusobacterium necrophorum is among the frequently detected anaerobic pathogens from clinical specimens associated with liver abscesses, skin and soft tissue infections, or oral abscesses. The antimicrobial therapy for this kind of infection needs to be optimized. Here, we examined the possibility of treating F. necrophorum-induced abscess wound infections with candidate therapeutics based on three endolysins with activity against a broad spectrum of aerobe Gram-negative pathogens. Antibacterial gel containing three Gram-negative bacteria-targeting endolysins, LysAm24, LysAp22, and LysECD7, was formulated for topical use. Abscess formation was induced in rabbits with F. necrophorum and caused systemic infection. The survival and lifespan of the animals, general parameters, and biochemical and hematological blood tests were analyzed to assess the effectiveness of the gel treatment for the wound infection. The administration of the investigated gel twice per day for 5 days resulted in less acute inflammation, with decreased leukocytes and segmented neutrophils in the blood, retardation of infection progression, and an almost two-fold increase in the lifespan of the animals compared to the placebo group. The results indicate that endolysin-based therapy is an effective approach to treat anaerobic bacterial infections. The use of endolysins as independent pharmaceuticals, or their combination with antibiotics, could significantly reduce the development of complications in infectious diseases caused by sensitive bacterial species.

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Candida albicans Uses Multiple Mechanisms To Acquire the Essential Metabolite Inositol during Infection

Infection and Immunity ◽

10.1128/iai.01514-07 ◽

2008 ◽

Vol 76 (6) ◽

pp. 2793-2801 ◽

Cited By ~ 35

Author(s):

Ying-Lien Chen ◽

Sarah Kauffman ◽

Todd B. Reynolds

Keyword(s):

Candida Albicans ◽

Mouse Model ◽

Double Mutant ◽

De Novo ◽

Systemic Infection ◽

Bloodstream Infections ◽

Wild Type Allele ◽

Transporter Gene ◽

Wild Type ◽

Life Threatening

ABSTRACT Candida albicans is an important cause of life-threatening systemic bloodstream infections in immunocompromised patients. In order to cause infections, C. albicans must be able to synthesize the essential metabolite inositol or acquire it from the host. Based on the similarity of C. albicans to Saccharomyces cerevisiae, it was predicted that C. albicans may generate inositol de novo, import it from the environment, or both. The C. albicans inositol synthesis gene INO1 (orf19.7585) and inositol transporter gene ITR1 (orf19.3526) were each disrupted. The ino1Δ/ino1Δ mutant was an inositol auxotroph, and the itr1Δ/itr1Δ mutant was unable to import inositol from the medium. Each of these mutants was fully virulent in a mouse model of systemic infection. It was not possible to generate an ino1Δ/ino1Δ itr1Δ/itr1Δ double mutant, suggesting that in the absence of these two genes, C. albicans could not acquire inositol and was nonviable. A conditional double mutant was created by replacing the remaining wild-type allele of ITR1 in an ino1Δ/ino1Δ itr1Δ/ITR1 strain with a conditionally expressed allele of ITR1 driven by the repressible MET3 promoter. The resulting ino1Δ/ino1Δ itr1Δ/PMET3 ::ITR1 strain was found to be nonviable in medium containing methionine and cysteine (which represses the PMET3 promoter), and it was avirulent in the mouse model of systemic candidiasis. These results suggest a model in which C. albicans has two equally effective mechanisms for obtaining inositol while in the host. It can either generate inositol de novo through Ino1p, or it can import it from the host through Itr1p.

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Yokukansan, a Traditional Japanese Medicine, Enhances the Glutamate Transporter GLT-1 Function in Cultured Rat Cortical Astrocytes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6804017 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Toshiyuki Ueki ◽

Zenji Kawakami ◽

Hitomi Kanno ◽

Yuji Omiya ◽

Kazushige Mizoguchi ◽

...

Keyword(s):

Glutamate Uptake ◽

Glutamate Transporter ◽

Culture Conditions ◽

Mrna Levels ◽

Extracellular Glutamate ◽

Cultured Astrocytes ◽

Traditional Japanese Medicine ◽

Uptake Activity ◽

The Brain ◽

Necrosis Factor

Astrocytes carry two glutamate transporters—GLAST and GLT-1—the latter of which is responsible for >90% of glutamate uptake activity in the brain; however, under culture conditions, the GLT-1 expression in astrocytes is exceedingly low, as is the glutamate uptake activity mediated by GLT-1. This study aimed to elucidate the effects of yokukansan (YKS) in relation to the GLT-1-mediated regulation of extracellular glutamate concentrations. Thus, we treated cultured astrocytes with tumor necrosis factor-α (TNF-α) and dibutyryl-cAMP (dBcAMP) (hereinafter, referred to as “TA”) to increase GLT-1 expression and then functionally examined how YKS would affect glutamate uptake ability derived from GLT-1. Contrary to expectations, although the TA treatments did not affect the uptake activity, YKS significantly augmented it. Conversely, GLAST-derived glutamate uptake was significantly reduced by TA treatments but was unaffected by YKS. Subsequently, we analyzed the GLT-1 protein and mRNA levels and found that TA treatments had significantly increased them, which were then further augmented by YKS. These findings suggest that YKS enhances GLT-1-derived glutamate transport functions in TA-treated cultured astrocytes and that this process entails increased GLT-1 protein and mRNA levels. This type of mechanism may contribute to the YKS-mediated regulation of extracellular glutamate concentrations.

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Bradyzoite-Specific Surface Antigen SRS9 Plays a Role in Maintaining Toxoplasma gondii Persistence in the Brain and in Host Control of Parasite Replication in the Intestine

Infection and Immunity ◽

10.1128/iai.01862-06 ◽

2007 ◽

Vol 75 (4) ◽

pp. 1626-1634 ◽

Cited By ~ 89

Author(s):

Seon-Kyeong Kim ◽

Ariela Karasov ◽

John C. Boothroyd

Keyword(s):

Toxoplasma Gondii ◽

Chronic Infection ◽

Acute Infection ◽

Surface Proteins ◽

Mammalian Host ◽

Wild Type ◽

Life Threatening ◽

Parasite Replication ◽

The Brain ◽

Developmental Switch

ABSTRACT Toxoplasma gondii is a ubiquitous parasite that persists for the life of a healthy mammalian host. A latent, chronic infection can reactivate upon immunosuppression and cause life-threatening diseases, such as encephalitis. A key to the pathogenesis is the parasite's interconversion between the tachyzoite (in acute infection) and bradyzoite (in chronic infection) stages. This developmental switch is marked by differential expression of numerous, closely related surface proteins belonging to the SRS (SAG1-related sequence) superfamily. To probe the functions of bradyzoite-specific SRSs, we created a bioluminescent strain lacking the expression of SRS9, one of the most abundant SRSs of the bradyzoite stage. Imaging of mice intraperitoneally infected with tachyzoites revealed that during an acute infection, wild-type and Δsrs9 strains replicated at similar rates, disseminated systemically following similar kinetics, and initially yielded similar brain cyst numbers. However, during a chronic infection, Δsrs9 cyst loads substantially decreased compared to those of the wild type, suggesting that SRS9 plays a role in maintaining parasite persistence in the brain. In oral infection with bradyzoite cysts, the Δsrs9 strain showed oral infectivity and dissemination patterns indistinguishable from those of the wild type. When chronically infected mice were treated with the immunosuppressant dexamethasone, however, the Δsrs9 strain reactivated in the intestinal tissue after only 8 to 9 days, versus 2 weeks for the wild-type strain. Thus, SRS9 appears to play an important role in both persistence in the brain and reactivation in the intestine. Possible mechanisms for this are discussed.

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CCK2 receptor nullification attenuates lipopolysaccharide-induced sickness behavior

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00156.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R112-R123 ◽

Cited By ~ 10

Author(s):

Tracey J. Weiland ◽

Nicholas J. Voudouris ◽

Stephen Kent

Keyword(s):

Body Weight ◽

Vagus Nerve ◽

Peripheral Nerves ◽

Critical Role ◽

Systemic Infection ◽

Sickness Behavior ◽

Receptor Activation ◽

Wild Type ◽

The Brain ◽

Cck2 Receptor

Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behavior after intraperitoneally delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CCK2/gastrin receptors (CCK2KO) and wild-type (WT) controls were administered LPS (50, 500, or 2,500 μg/kg; serotype 0111:B4; ip). Results indicate a role for CCK2 receptor activation in the initiation and maintenance of LPS-induced sickness behavior. Compared with WT controls, CCK2KO mice were significantly less affected by LPS on measures of body temperature, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CCK2 receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in nonvagal routes of immune-brain communication is suggested.

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Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity

The Journal of Cell Biology ◽

10.1083/jcb.200508072 ◽

2005 ◽

Vol 171 (6) ◽

pp. 1001-1012 ◽

Cited By ~ 280

Author(s):

Ji-Yeon Shin ◽

Zhi-Hui Fang ◽

Zhao-Xue Yu ◽

Chuan-En Wang ◽

Shi-Hua Li ◽

...

Keyword(s):

Glial Cells ◽

Glutamate Uptake ◽

Glutamate Excitotoxicity ◽

Mutant Huntingtin ◽

Wild Type ◽

Spiny Neurons ◽

Cultured Astrocytes ◽

Preferential Loss ◽

The Brain

Huntington disease (HD) is characterized by the preferential loss of striatal medium-sized spiny neurons (MSNs) in the brain. Because MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be largely influenced by the capacity of glial cells to remove extracellular glutamate. However, little is known about the role of glia in HD neuropathology. Here, we report that mutant huntingtin accumulates in glial nuclei in HD brains and decreases the expression of glutamate transporters. As a result, mutant huntingtin (htt) reduces glutamate uptake in cultured astrocytes and HD mouse brains. In a neuron–glia coculture system, wild-type glial cells protected neurons against mutant htt-mediated neurotoxicity, whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes decreased their protection of neurons against glutamate excitotoxicity. These findings suggest that decreased glutamate uptake caused by glial mutant htt may critically contribute to neuronal excitotoxicity in HD.

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Advantages of Complementary Stereo Images as Viewed with the Low-Temperature Field-Emission SEM

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100131206 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1314-1315

Author(s):

William P. Wergin ◽

Eric F. Erbe

Keyword(s):

Fold Increase ◽

Horizontal Displacement ◽

Three Dimensions ◽

Stereo Image ◽

Stereo Pair ◽

Sem Micrograph ◽

Left And Right ◽

The Common ◽

The Brain ◽

Pair Analysis

The eye-brain complex allows those of us with normal vision to perceive and evaluate our surroundings in three-dimensions (3-D). The principle factor that makes this possible is parallax - the horizontal displacement of objects that results from the independent views that the left and right eyes detect and simultaneously transmit to the brain for superimposition. The common SEM micrograph is a 2-D representation of a 3-D specimen. Depriving the brain of the 3-D view can lead to erroneous conclusions about the relative sizes, positions and convergence of structures within a specimen. In addition, Walter has suggested that the stereo image contains information equivalent to a two-fold increase in magnification over that found in a 2-D image. Because of these factors, stereo pair analysis should be routinely employed when studying specimens.Imaging complementary faces of a fractured specimen is a second method by which the topography of a specimen can be more accurately evaluated.

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Fact file 1: Critical care and emergency medicine

10.1093/oso/9780198792079.003.0014 ◽

2017 ◽

Author(s):

Daisy Fancourt

Keyword(s):

Emergency Medicine ◽

Critical Care ◽

Sports Medicine ◽

Orthopaedic Surgery ◽

Extreme Environment ◽

Disaster Medicine ◽

Medical Attention ◽

Life Threatening ◽

Medical Disciplines ◽

The Brain

Emergency medicine involves the care of patients who require immediate medical attention. The specialty encompasses a broad range of medical disciplines, including anaesthesia, cardiology (a field related to the heart), neurology (a field related to the brain), plastic surgery, orthopaedic surgery (surgery relating to the bones or muscles), and cardiothoracic surgery (surgery relating to the heart, chest, or lungs). There are also a number of subspecialties including extreme environment medicine, disaster medicine and sports medicine. Related to emergency medicine is the specialty of critical care medicine, which is concerned with the care of patients with life-threatening conditions often treated in intensive care settings....

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