The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response
The obligate intracellular parasite Toxoplasma gondii secretes effector proteins into the host cell that manipulate the immune response allowing it to establish a chronic infection. Crosses between the types I, II and III strains, which are prevalent in North America and Europe, have identified seve...
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Public Library of Science
2012
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| Online Access: | http://hdl.handle.net/1721.1/72334 https://orcid.org/0000-0002-9547-3251 |
| _version_ | 1811072130211643392 |
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| author | Niedelman, Wendy Leah Rosowski, Emily Elizabeth Sprokholt, Joris Kasper Lim, Daniel Cham-Chin Arenas, Ailan Farid Melo, Mariane Bandeira Spooner, Eric Saeij, Jeroen Gold, Daniel A. Yaffe, Michael B |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Niedelman, Wendy Leah Rosowski, Emily Elizabeth Sprokholt, Joris Kasper Lim, Daniel Cham-Chin Arenas, Ailan Farid Melo, Mariane Bandeira Spooner, Eric Saeij, Jeroen Gold, Daniel A. Yaffe, Michael B |
| author_sort | Niedelman, Wendy Leah |
| collection | MIT |
| description | The obligate intracellular parasite Toxoplasma gondii secretes effector proteins into the host cell that manipulate the immune response allowing it to establish a chronic infection. Crosses between the types I, II and III strains, which are prevalent in North America and Europe, have identified several secreted effectors that determine strain differences in mouse virulence. The polymorphic rhoptry protein kinase ROP18 was recently shown to determine the difference in virulence between type I and III strains by phosphorylating and inactivating the interferon-γ (IFNγ)-induced immunity-related GTPases (IRGs) that promote killing by disrupting the parasitophorous vacuole membrane (PVM) in murine cells. The polymorphic pseudokinase ROP5 determines strain differences in virulence through an unknown mechanism. Here we report that ROP18 can only inhibit accumulation of the IRGs on the PVM of strains that also express virulent ROP5 alleles. In contrast, specific ROP5 alleles can reduce IRG coating even in the absence of ROP18 expression and can directly interact with one or more IRGs. We further show that the allelic combination of ROP18 and ROP5 also determines IRG evasion and virulence of strains belonging to other lineages besides types I, II and III. However, neither ROP18 nor ROP5 markedly affect survival in IFNγ-activated human cells, which lack the multitude of IRGs present in murine cells. These findings suggest that ROP18 and ROP5 have specifically evolved to block the IRGs and are unlikely to have effects in species that do not have the IRG system, such as humans. |
| first_indexed | 2024-09-23T09:01:23Z |
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| id | mit-1721.1/72334 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:01:23Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/723342022-09-26T09:52:05Z The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response Niedelman, Wendy Leah Rosowski, Emily Elizabeth Sprokholt, Joris Kasper Lim, Daniel Cham-Chin Arenas, Ailan Farid Melo, Mariane Bandeira Spooner, Eric Saeij, Jeroen Gold, Daniel A. Yaffe, Michael B Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Yaffe, Michael B. Niedelman, Wendy Leah Gold, Daniel Rosowski, Emily Elizabeth Sprokholt, Joris Kasper Lim, Daniel Cham-Chin Melo, Mariane Bandeira Spooner, Eric Yaffe, Michael B. Saeij, Jeroen The obligate intracellular parasite Toxoplasma gondii secretes effector proteins into the host cell that manipulate the immune response allowing it to establish a chronic infection. Crosses between the types I, II and III strains, which are prevalent in North America and Europe, have identified several secreted effectors that determine strain differences in mouse virulence. The polymorphic rhoptry protein kinase ROP18 was recently shown to determine the difference in virulence between type I and III strains by phosphorylating and inactivating the interferon-γ (IFNγ)-induced immunity-related GTPases (IRGs) that promote killing by disrupting the parasitophorous vacuole membrane (PVM) in murine cells. The polymorphic pseudokinase ROP5 determines strain differences in virulence through an unknown mechanism. Here we report that ROP18 can only inhibit accumulation of the IRGs on the PVM of strains that also express virulent ROP5 alleles. In contrast, specific ROP5 alleles can reduce IRG coating even in the absence of ROP18 expression and can directly interact with one or more IRGs. We further show that the allelic combination of ROP18 and ROP5 also determines IRG evasion and virulence of strains belonging to other lineages besides types I, II and III. However, neither ROP18 nor ROP5 markedly affect survival in IFNγ-activated human cells, which lack the multitude of IRGs present in murine cells. These findings suggest that ROP18 and ROP5 have specifically evolved to block the IRGs and are unlikely to have effects in species that do not have the IRG system, such as humans. 2012-08-22T20:50:10Z 2012-08-22T20:50:10Z 2012-06 2011-12 Article http://purl.org/eprint/type/JournalArticle 1553-7366 1553-7374 http://hdl.handle.net/1721.1/72334 Niedelman, Wendy et al. “The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma Gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response.” Ed. Dominique Soldati-Favre. PLoS Pathogens 8.6 (2012): e1002784. Web. https://orcid.org/0000-0002-9547-3251 en_US http://dx.doi.org/10.1371/journal.ppat.1002784 PloS Pathogens Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Niedelman, Wendy Leah Rosowski, Emily Elizabeth Sprokholt, Joris Kasper Lim, Daniel Cham-Chin Arenas, Ailan Farid Melo, Mariane Bandeira Spooner, Eric Saeij, Jeroen Gold, Daniel A. Yaffe, Michael B The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title_full | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title_fullStr | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title_full_unstemmed | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title_short | The Rhoptry Proteins ROP18 and ROP5 Mediate Toxoplasma gondii Evasion of the Murine, But Not the Human, Interferon-Gamma Response |
| title_sort | rhoptry proteins rop18 and rop5 mediate toxoplasma gondii evasion of the murine but not the human interferon gamma response |
| url | http://hdl.handle.net/1721.1/72334 https://orcid.org/0000-0002-9547-3251 |
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