Document Detail


CD73-generated adenosine facilitates Toxoplasma gondii differentiation to long-lived tissue cysts in the central nervous system.
MedLine Citation:
PMID:  22988118     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Deeqa A Mahamed; Jeffrey H Mills; Charlotte E Egan; Eric Y Denkers; Margaret S Bynoe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-09-17
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-03     Completed Date:  2012-12-31     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16312-7     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
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MeSH Terms
Descriptor/Qualifier:
5'-Nucleotidase / genetics
Adenosine / deficiency,  genetics,  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*,  prevention & control
Grant Support
ID/Acronym/Agency:
R01 AI50617/AI/NIAID NIH HHS; R01 NS05301-04S4/NS/NINDS NIH HHS; R01 NS053011/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 50-02-2/Dexamethasone; 58-61-7/Adenosine; EC 3.1.3.5/5'-Nucleotidase
Comments/Corrections

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