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Article ; Online: CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection.

Mahamed, Deeqa A / Toussaint, Leon E / Bynoe, Margaret S

2015 Volume 83, Issue 2, Page(s) 721–729

Abstract: As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii evades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ... ...

Abstract	As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii evades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection with T. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected wild-type (WT) and CD73(-/-) mice with T. gondii cysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73(-/-) mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) protected CD73(-/-) mice against T. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73(-/-) mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limiting T. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A(2A) were more susceptible to immunopathology during intraperitoneal infection with T. gondii than WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.
MeSH term(s)	5'-Nucleotidase/genetics ; 5'-Nucleotidase/metabolism ; Adenosine/genetics ; Adenosine/immunology ; Adenosine-5'-(N-ethylcarboxamide)/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Inflammation/genetics ; Inflammation/immunology ; Inflammation Mediators/blood ; Interleukin-1beta/blood ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophil Infiltration/immunology ; Neutrophils/immunology ; Nitric Oxide/biosynthesis ; Purinergic P1 Receptor Agonists/pharmacology ; Toxoplasma/immunology ; Toxoplasmosis/immunology ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Antineoplastic Agents ; Inflammation Mediators ; Interleukin-1beta ; Purinergic P1 Receptor Agonists ; Tumor Necrosis Factor-alpha ; Nitric Oxide (31C4KY9ESH) ; Adenosine-5'-(N-ethylcarboxamide) (35920-39-9) ; 5'-Nucleotidase (EC 3.1.3.5) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2015-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.02536-14
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis.

Mills, Jeffrey H / Alabanza, Leah M / Mahamed, Deeqa A / Bynoe, Margaret S

Journal of neuroinflammation

2012 Volume 9, Page(s) 193

Abstract: Background: Multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are debilitating neuroinflammatory diseases mediated by lymphocyte entry into the central nervous system (CNS). While it is not known what triggers ... ...

Abstract	Background: Multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are debilitating neuroinflammatory diseases mediated by lymphocyte entry into the central nervous system (CNS). While it is not known what triggers lymphocyte entry into the CNS during neuroinflammation, blockade of lymphocyte migration has been shown to be effective in controlling neuroinflammatory diseases. Since we have previously shown that extracellular adenosine is a key mediator of lymphocyte migration into the CNS during EAE progression, we wanted to determine which factors are regulated by adenosine to modulate EAE development. Methods: We performed a genetic analysis of wild type and CD73-/- (that are unable to produce extracellular adenosine and are protected from EAE development) to identify factors that are both important for EAE development and controlled by extracellular adenosine signaling. Results: We show that extracellular adenosine triggered lymphocyte migration into the CNS by inducing the expression of the specialized chemokine/adhesion molecule CX3CL1 at the choroid plexus. In wild type mice, CX3CL1 is upregulated in the brain on Day 10 post EAE induction, which corresponds with initial CNS lymphocyte infiltration and the acute stage of EAE. Conversely, mice that cannot synthesize extracellular adenosine (CD73-/- mice) do not upregulate CX3CL1 in the brain following EAE induction and are protected from EAE development and its associated lymphocyte infiltration. Additionally, blockade of the A2A adenosine receptor following EAE induction prevents disease development and the induction of brain CX3CL1 expression. The CX3CL1 induced during EAE is found on the choroid plexus, which is the barrier between the blood and cerebral spinal fluid in the brain and is a prime entry point into the CNS for immune cells. Furthermore, CX3CL1 expression can be induced in the brains of mice and in choroid plexus cell line following A2A adenosine receptor agonist administration. Most importantly, we show that CX3CL1 blockade protects against EAE development and inhibits lymphocyte entry into the CNS. Conclusions: We conclude that extracellular adenosine is an endogenous modulator of neuroinflammation during EAE that induces CX3CL1 at the choroid plexus to trigger lymphocyte entry into the brain.
MeSH term(s)	Adenosine/biosynthesis ; Animals ; Brain/metabolism ; Cells, Cultured ; Chemokine CX3CL1/biosynthesis ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Extracellular Fluid/metabolism ; Gene Expression Regulation/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Adenosine A2A/metabolism ; Signal Transduction/physiology
Chemical Substances	Chemokine CX3CL1 ; Cx3cl1 protein, mouse ; Receptor, Adenosine A2A ; Adenosine (K72T3FS567)
Language	English
Publishing date	2012-08-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/1742-2094-9-193
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis

Mills Jeffrey H / Alabanza Leah M / Mahamed Deeqa A / Bynoe Margaret S

Journal of Neuroinflammation, Vol 9, Iss 1, p

2012 Volume 193

Abstract: Abstract Background Multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are debilitating neuroinflammatory diseases mediated by lymphocyte entry into the central nervous system (CNS). While it is not known what ... ...

Abstract	Abstract Background Multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are debilitating neuroinflammatory diseases mediated by lymphocyte entry into the central nervous system (CNS). While it is not known what triggers lymphocyte entry into the CNS during neuroinflammation, blockade of lymphocyte migration has been shown to be effective in controlling neuroinflammatory diseases. Since we have previously shown that extracellular adenosine is a key mediator of lymphocyte migration into the CNS during EAE progression, we wanted to determine which factors are regulated by adenosine to modulate EAE development. Methods We performed a genetic analysis of wild type and CD73−/− (that are unable to produce extracellular adenosine and are protected from EAE development) to identify factors that are both important for EAE development and controlled by extracellular adenosine signaling. Results We show that extracellular adenosine triggered lymphocyte migration into the CNS by inducing the expression of the specialized chemokine/adhesion molecule CX3CL1 at the choroid plexus. In wild type mice, CX3CL1 is upregulated in the brain on Day 10 post EAE induction, which corresponds with initial CNS lymphocyte infiltration and the acute stage of EAE. Conversely, mice that cannot synthesize extracellular adenosine (CD73−/− mice) do not upregulate CX3CL1 in the brain following EAE induction and are protected from EAE development and its associated lymphocyte infiltration. Additionally, blockade of the A2A adenosine receptor following EAE induction prevents disease development and the induction of brain CX3CL1 expression. The CX3CL1 induced during EAE is found on the choroid plexus, which is the barrier between the blood and cerebral spinal fluid in the brain and is a prime entry point into the CNS for immune cells. Furthermore, CX3CL1 expression can be induced in the brains of mice and in choroid plexus cell line following A2A adenosine receptor agonist administration. Most importantly, we show that CX3CL1 blockade protects against EAE development and inhibits lymphocyte entry into the CNS. Conclusions We conclude that extracellular adenosine is an endogenous modulator of neuroinflammation during EAE that induces CX3CL1 at the choroid plexus to trigger lymphocyte entry into the brain.
Keywords	Extracellular adenosine ; CD73 ; A2A adenosine receptor ; CX3CL1 (fractalkine) ; Experimental autoimmune encephalomyelitis ; Multiple sclerosis ; Neuroinflammation ; Choroid plexus ; Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; DOAJ:Neurology
Subject code	572
Language	English
Publishing date	2012-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system.

Mahamed, Deeqa A / Mills, Jeffrey H / Egan, Charlotte E / Denkers, Eric Y / Bynoe, Margaret S

Proceedings of the National Academy of Sciences of the United States of America

2012 Volume 109, Issue 40, Page(s) 16312–16317

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	5'-Nucleotidase/genetics ; Adenosine/deficiency ; Adenosine/genetics ; Adenosine/metabolism ; Analysis of Variance ; Animals ; Central Nervous System/parasitology ; Cysts/parasitology ; DNA Primers/genetics ; Dexamethasone ; Female ; Flow Cytometry ; Kinetics ; Life Cycle Stages/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Fluorescence ; Polymerase Chain Reaction ; Toxoplasma/physiology ; Toxoplasmosis/genetics ; Toxoplasmosis/prevention & control
Chemical Substances	DNA Primers ; Dexamethasone (7S5I7G3JQL) ; 5'-Nucleotidase (EC 3.1.3.5) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2012-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1205589109
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1148: Show issues

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Article ; Online: CD73 is critical for the resolution of murine colonic inflammation.

Bynoe, Margaret S / Waickman, Adam T / Mahamed, Deeqa A / Mueller, Cynthia / Mills, Jeffrey H / Czopik, Agnieszka

Journal of biomedicine & biotechnology

2012 Volume 2012, Page(s) 260983

Abstract: CD73 is a glycosyl-phosphatidylinositol-(GPI-) linked membrane protein that catalyzes the extracellular dephosphorylation of adenosine monophosphate (AMP) to adenosine. Adenosine is a negative regulator of inflammation and prevents excessive cellular ... ...

Abstract	CD73 is a glycosyl-phosphatidylinositol-(GPI-) linked membrane protein that catalyzes the extracellular dephosphorylation of adenosine monophosphate (AMP) to adenosine. Adenosine is a negative regulator of inflammation and prevents excessive cellular damage. We investigated the role of extracellular adenosine in the intestinal mucosa during the development of Dextran-Sulfate-Sodium-(DSS-)salt-induced colitis in mice that lack CD73 (CD73(-/-)) and are unable to synthesize extracellular adenosine. We have found that, compared to wild-type (WT) mice, CD73(-/-) mice are highly susceptible to DSS-induced colitis. CD73(-/-) mice exhibit pronounced weight loss, slower weight recovery, an increase in gut permeability, a decrease in expression of tight junctional adhesion molecules, as well as unresolved inflammation following the removal of DSS. Moreover, colonic epithelia in CD73(-/-) mice exhibited increased TLR9 expression, high levels of IL-1β and TNF-α, and constitutive activation of NF-κB. We conclude that CD73 expression in the colon is critical for regulating the magnitude and the resolution of colonic immune responses.
MeSH term(s)	5'-Nucleotidase/deficiency ; 5'-Nucleotidase/metabolism ; Animals ; CD4-Positive T-Lymphocytes/immunology ; Colitis/enzymology ; Colitis/immunology ; Colitis/pathology ; Colitis/physiopathology ; Colon/enzymology ; Colon/immunology ; Colon/pathology ; Colon/physiopathology ; GPI-Linked Proteins/deficiency ; GPI-Linked Proteins/metabolism ; Inflammation/enzymology ; Inflammation/pathology ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/pathology ; Interleukin-1beta/biosynthesis ; Intestinal Mucosa/enzymology ; Intestinal Mucosa/pathology ; Leukocyte Common Antigens/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Permeability ; Recovery of Function ; Tight Junction Proteins/metabolism ; Toll-Like Receptor 9/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; Up-Regulation
Chemical Substances	GPI-Linked Proteins ; Interleukin-1beta ; NF-kappa B ; Tight Junction Proteins ; Tlr9 protein, mouse ; Toll-Like Receptor 9 ; Tumor Necrosis Factor-alpha ; Leukocyte Common Antigens (EC 3.1.3.48) ; 5'-Nucleotidase (EC 3.1.3.5) ; Nt5e protein, mouse (EC 3.1.3.5)
Language	English
Publishing date	2012-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2052552-7
ISSN	1110-7251 ; 1110-7243
ISSN (online)	1110-7251
ISSN	1110-7243
DOI	10.1155/2012/260983
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Article: G(-) anaerobes-reactive CD4+ T-cells trigger RANKL-mediated enhanced alveolar bone loss in diabetic NOD mice.

Mahamed, Deeqa A / Marleau, Annette / Alnaeeli, Mawadda / Singh, Bhagirath / Zhang, Xiaoxia / Penninger, Joseph M / Teng, Yen-Tung A

Diabetes

2005 Volume 54, Issue 5, Page(s) 1477–1486

Abstract: Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell-mediated immunity to enhanced alveolar bone loss during periodontal infection ...

Abstract	Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell-mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(-) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans-reactive CD4+ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor kappaB ligand (RANKL) expression. When diabetic mice are treated with the RANKL antagonist osteoprotegerin (OPG), there is a significant reversal of alveolar bone loss, as well as reduced RANKL expression in A. actinomycetemcomitans-reactive CD4+ T-cells. This study clearly describes the impact of autoimmunity to anaerobic infection in an experimental periodontitis model of type 1 diabetes. Thus, microorganism-reactive CD4+ T-cells and the RANKL-OPG axis provide the molecular basis of the advanced periodontal breakdown in diabetes and, therefore, OPG may hold therapeutic potential for treating bone loss in diabetic subjects at high risk.
MeSH term(s)	Actinobacillus Infections/immunology ; Aggregatibacter actinomycetemcomitans ; Alveolar Bone Loss/microbiology ; Alveolar Bone Loss/physiopathology ; Animals ; Bacteria, Anaerobic ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/microbiology ; Carrier Proteins/physiology ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/microbiology ; Glycoproteins/physiology ; Humans ; Membrane Glycoproteins/physiology ; Mice ; Mice, Inbred NOD ; Osteoprotegerin ; Prediabetic State/immunology ; Prediabetic State/microbiology ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Receptors, Cytoplasmic and Nuclear/physiology ; Receptors, Tumor Necrosis Factor/physiology
Chemical Substances	Carrier Proteins ; Glycoproteins ; Membrane Glycoproteins ; Osteoprotegerin ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Receptors, Cytoplasmic and Nuclear ; Receptors, Tumor Necrosis Factor ; TNFRSF11A protein, human ; TNFRSF11B protein, human ; TNFSF11 protein, human ; Tnfrsf11a protein, mouse ; Tnfrsf11b protein, mouse ; Tnfsf11 protein, mouse
Language	English
Publishing date	2005-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/diabetes.54.5.1477
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Article: CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system

Mahamed, Deeqa A. / Mills, Jeffrey H. / Egan, Charlotte E. / Denkers, Eric Y. / Bynoe, Margaret S.

Proceedings of the National Academy of Sciences of the United States of America

Volume v. 109,, Issue no. 4

Abstract	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.
Keywords	purinergic receptors ; parasites ; agonists ; pathogenesis ; humans ; pathogens ; purines ; toxoplasmosis ; mice ; adenosine ; Toxoplasma gondii ; tachyzoites ; fibroblasts ; hosts ; astrocytes ; brain ; energy ; pH
Language	English
Document type	Article
ISSN	0027-8424
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article ; Online: CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection.

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Article ; Online: Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis.

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Article ; Online: Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis

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Article ; Online: CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system.

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Article ; Online: CD73 is critical for the resolution of murine colonic inflammation.

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Article: G(-) anaerobes-reactive CD4+ T-cells trigger RANKL-mediated enhanced alveolar bone loss in diabetic NOD mice.

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Article: CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system

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