Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death.
Toxoplasma gondii is a natural intracellular protozoal pathogen of mice and other small mammals. After infection, the parasite replicates freely in many cell types (tachyzoite stage) before undergoing a phase transition and encysting in brain and muscle (bradyzoite stage). In the mouse, early immune...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-02-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197351/pdf/?tool=EBI |
| _version_ | 1818682112242352128 |
|---|---|
| author | Yang O Zhao Aliaksandr Khaminets Julia P Hunn Jonathan C Howard |
| author_facet | Yang O Zhao Aliaksandr Khaminets Julia P Hunn Jonathan C Howard |
| author_sort | Yang O Zhao |
| collection | DOAJ |
| description | Toxoplasma gondii is a natural intracellular protozoal pathogen of mice and other small mammals. After infection, the parasite replicates freely in many cell types (tachyzoite stage) before undergoing a phase transition and encysting in brain and muscle (bradyzoite stage). In the mouse, early immune resistance to the tachyzoite stage is mediated by the family of interferon-inducible immunity-related GTPases (IRG proteins), but little is known of the nature of this resistance. We reported earlier that IRG proteins accumulate on intracellular vacuoles containing the pathogen, and that the vacuolar membrane subsequently ruptures. In this report, live-cell imaging microscopy has been used to follow this process and its consequences in real time. We show that the rupture of the vacuole is inevitably followed by death of the intracellular parasite, shown by its permeability to cytosolic protein markers. Death of the parasite is followed by the death of the infected cell. The death of the cell has features of pyronecrosis, including membrane permeabilisation and release of the inflammatory protein, HMGB1, but caspase-1 cleavage is not detected. This sequence of events occurs on a large scale only following infection of IFNgamma-induced cells with an avirulent strain of T. gondii, and is reduced by expression of a dominant negative mutant IRG protein. Cells infected by virulent strains rarely undergo necrosis. We did not find autophagy to play any role in the key steps leading to the death of the parasite. We conclude that IRG proteins resist infection by avirulent T. gondii by a novel mechanism involving disruption of the vacuolar membrane, which in turn ultimately leads to the necrotic death of the infected cell. |
| first_indexed | 2024-12-17T10:13:40Z |
| format | Article |
| id | doaj.art-44cf9c89c4704ba08ad7a4354bd3a5f4 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-17T10:13:40Z |
| publishDate | 2009-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-44cf9c89c4704ba08ad7a4354bd3a5f42022-12-21T21:52:58ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742009-02-0152e100028810.1371/journal.ppat.1000288Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death.Yang O ZhaoAliaksandr KhaminetsJulia P HunnJonathan C HowardToxoplasma gondii is a natural intracellular protozoal pathogen of mice and other small mammals. After infection, the parasite replicates freely in many cell types (tachyzoite stage) before undergoing a phase transition and encysting in brain and muscle (bradyzoite stage). In the mouse, early immune resistance to the tachyzoite stage is mediated by the family of interferon-inducible immunity-related GTPases (IRG proteins), but little is known of the nature of this resistance. We reported earlier that IRG proteins accumulate on intracellular vacuoles containing the pathogen, and that the vacuolar membrane subsequently ruptures. In this report, live-cell imaging microscopy has been used to follow this process and its consequences in real time. We show that the rupture of the vacuole is inevitably followed by death of the intracellular parasite, shown by its permeability to cytosolic protein markers. Death of the parasite is followed by the death of the infected cell. The death of the cell has features of pyronecrosis, including membrane permeabilisation and release of the inflammatory protein, HMGB1, but caspase-1 cleavage is not detected. This sequence of events occurs on a large scale only following infection of IFNgamma-induced cells with an avirulent strain of T. gondii, and is reduced by expression of a dominant negative mutant IRG protein. Cells infected by virulent strains rarely undergo necrosis. We did not find autophagy to play any role in the key steps leading to the death of the parasite. We conclude that IRG proteins resist infection by avirulent T. gondii by a novel mechanism involving disruption of the vacuolar membrane, which in turn ultimately leads to the necrotic death of the infected cell.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197351/pdf/?tool=EBI |
| spellingShingle | Yang O Zhao Aliaksandr Khaminets Julia P Hunn Jonathan C Howard Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS Pathogens |
| title | Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. |
| title_full | Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. |
| title_fullStr | Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. |
| title_full_unstemmed | Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. |
| title_short | Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. |
| title_sort | disruption of the toxoplasma gondii parasitophorous vacuole by ifngamma inducible immunity related gtpases irg proteins triggers necrotic cell death |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197351/pdf/?tool=EBI |
| work_keys_str_mv | AT yangozhao disruptionofthetoxoplasmagondiiparasitophorousvacuolebyifngammainducibleimmunityrelatedgtpasesirgproteinstriggersnecroticcelldeath AT aliaksandrkhaminets disruptionofthetoxoplasmagondiiparasitophorousvacuolebyifngammainducibleimmunityrelatedgtpasesirgproteinstriggersnecroticcelldeath AT juliaphunn disruptionofthetoxoplasmagondiiparasitophorousvacuolebyifngammainducibleimmunityrelatedgtpasesirgproteinstriggersnecroticcelldeath AT jonathanchoward disruptionofthetoxoplasmagondiiparasitophorousvacuolebyifngammainducibleimmunityrelatedgtpasesirgproteinstriggersnecroticcelldeath |