| The human fungal pathogen Cryptococcus neoformans escapes macrophages by a phagosome emptying mechanism that is inhibited by Arp2/3 complex-mediated actin polymerisation. | |
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MedLine Citation:
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PMID: 20714349 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin 'flashes' occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism. |
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Authors:
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Simon A Johnston; Robin C May |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-12 |
Journal Detail:
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Title: PLoS pathogens Volume: 6 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-08-17 Completed Date: 2010-12-02 Revised Date: 2011-08-31 |
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: e1001041 Citation Subset: IM |
Affiliation:
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School of Biosciences, College of Life and Environmental Sciences, The University of Birmingham, Birmingham, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Actin-Related Protein 2-3 Complex
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metabolism* Actins / metabolism* Animals Cryptococcosis / immunology*, microbiology Cryptococcus neoformans / immunology, pathogenicity* Cytoskeleton / metabolism Green Fluorescent Proteins Humans Image Processing, Computer-Assisted Immune Evasion / immunology Macrophages / immunology, metabolism, microbiology* Mice Microscopy, Confocal Phagosomes / metabolism, microbiology* |
| Grant Support | |
ID/Acronym/Agency:
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088148MF//Wellcome Trust; G0601171//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Actin-Related Protein 2-3 Complex; 0/Actins; 147336-22-9/Green Fluorescent Proteins |
| Comments/Corrections | |
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