| The Trypanosoma cruzi protease cruzain mediates immune evasion. | |
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MedLine Citation:
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PMID: 21909255 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Trypanosoma cruzi is the causative agent of Chagas' disease. Novel chemotherapy with the drug K11777 targets the major cysteine protease cruzain and disrupts amastigote intracellular development. Nevertheless, the biological role of the protease in infection and pathogenesis remains unclear as cruzain gene knockout failed due to genetic redundancy. A role for the T. cruzi cysteine protease cruzain in immune evasion was elucidated in a comparative study of parental wild type- and cruzain-deficient parasites. Wild type T. cruzi did not activate host macrophages during early infection (<60 min) and no increase in ∼P iκB was detected. The signaling factor NF-κB P65 colocalized with cruzain on the cell surface of intracellular wild type parasites, and was proteolytically cleaved. No significant IL-12 expression occurred in macrophages infected with wild type T. cruzi and treated with LPS and BFA, confirming impairment of macrophage activation pathways. In contrast, cruzain-deficient parasites induced macrophage activation, detectable iκB phosphorylation, and nuclear NF-κB P65 localization. These parasites were unable to develop intracellularly and survive within macrophages. IL 12 expression levels in macrophages infected with cruzain-deficient T. cruzi were comparable to LPS activated controls. Thus cruzain hinders macrophage activation during the early (<60 min) stages of infection, by interruption of the NF-κB P65 mediated signaling pathway. These early events allow T. cruzi survival and replication, and may lead to the spread of infection in acute Chagas' disease. |
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Authors:
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Patricia S Doyle; Yuan M Zhou; Ivy Hsieh; Doron C Greenbaum; James H McKerrow; Juan C Engel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-09-01 |
Journal Detail:
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Title: PLoS pathogens Volume: 7 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-09-12 Completed Date: 2012-01-05 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 101238921 Medline TA: PLoS Pathog Country: United States |
Other Details:
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Languages: eng Pagination: e1002139 Citation Subset: IM |
Affiliation:
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Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arginase / biosynthesis Cysteine Endopeptidases / deficiency, physiology* Dipeptides / pharmacology Humans I-kappa B Proteins / metabolism Immune Evasion / physiology* Interleukin-12 / biosynthesis Lipopolysaccharides / pharmacology Macrophage Activation / drug effects Macrophages / drug effects, metabolism, parasitology* Mice NF-kappa B / metabolism Protozoan Proteins / physiology* Trypanosoma cruzi / drug effects, genetics Vinyl Compounds / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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AI 35707/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dipeptides; 0/I-kappa B Proteins; 0/Lipopolysaccharides; 0/N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; 0/NF-kappa B; 0/Protozoan Proteins; 0/Vinyl Compounds; 187348-17-0/Interleukin-12; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/cruzain, Trypanosoma cruzi; EC 3.5.3.1/Arginase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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