Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein
NF-κB is an integral component of the immune response to Toxoplasma gondii. Although evidence exists that T. gondii can directly modulate the NF-κB pathway, the parasite-derived effectors involved are unknown. We determined that type II strains of T. gondii activate more NF-κB than type I or type II...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Rockefeller University Press
2011
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| Online Access: | http://hdl.handle.net/1721.1/65419 |
| _version_ | 1826217050449641472 |
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| author | Rosowski, Emily Elizabeth Lu, Diana Julien, Lindsay Rodda, Lauren B. Gaiser, Rogier A. Saeij, Jeroen Jensen, Kirk D. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Rosowski, Emily Elizabeth Lu, Diana Julien, Lindsay Rodda, Lauren B. Gaiser, Rogier A. Saeij, Jeroen Jensen, Kirk D. |
| author_sort | Rosowski, Emily Elizabeth |
| collection | MIT |
| description | NF-κB is an integral component of the immune response to Toxoplasma gondii. Although evidence exists that T. gondii can directly modulate the NF-κB pathway, the parasite-derived effectors involved are unknown. We determined that type II strains of T. gondii activate more NF-κB than type I or type III strains, and using forward genetics we found that this difference is a result of the polymorphic protein GRA15, a novel dense granule protein which T. gondii secretes into the host cell upon invasion. A GRA15-deficient type II strain has a severe defect in both NF-κB nuclear translocation and NF-κB–mediated transcription. Furthermore, human cells expressing type II GRA15 also activate NF-κB, demonstrating that GRA15 alone is sufficient for NF-κB activation. Along with the rhoptry protein ROP16, GRA15 is responsible for a large part of the strain differences in the induction of IL-12 secretion by infected mouse macrophages. In vivo bioluminescent imaging showed that a GRA15-deficient type II strain grows faster compared with wild-type, most likely through its reduced induction of IFN-γ. These results show for the first time that a dense granule protein can modulate host signaling pathways, and dense granule proteins can therefore join rhoptry proteins in T. gondii’s host cell–modifying arsenal. |
| first_indexed | 2024-09-23T16:57:15Z |
| format | Article |
| id | mit-1721.1/65419 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:57:15Z |
| publishDate | 2011 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | mit-1721.1/654192022-09-29T22:37:28Z Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein Rosowski, Emily Elizabeth Lu, Diana Julien, Lindsay Rodda, Lauren B. Gaiser, Rogier A. Saeij, Jeroen Jensen, Kirk D. Massachusetts Institute of Technology. Department of Biology Saeij, Jeroen Rosowski, Emily Elizabeth Lu, Diana Julien, Lindsay Rodda, Lauren B. Gaiser, Rogier A. Jensen, Kirk D. C. Saeij, Jeroen NF-κB is an integral component of the immune response to Toxoplasma gondii. Although evidence exists that T. gondii can directly modulate the NF-κB pathway, the parasite-derived effectors involved are unknown. We determined that type II strains of T. gondii activate more NF-κB than type I or type III strains, and using forward genetics we found that this difference is a result of the polymorphic protein GRA15, a novel dense granule protein which T. gondii secretes into the host cell upon invasion. A GRA15-deficient type II strain has a severe defect in both NF-κB nuclear translocation and NF-κB–mediated transcription. Furthermore, human cells expressing type II GRA15 also activate NF-κB, demonstrating that GRA15 alone is sufficient for NF-κB activation. Along with the rhoptry protein ROP16, GRA15 is responsible for a large part of the strain differences in the induction of IL-12 secretion by infected mouse macrophages. In vivo bioluminescent imaging showed that a GRA15-deficient type II strain grows faster compared with wild-type, most likely through its reduced induction of IFN-γ. These results show for the first time that a dense granule protein can modulate host signaling pathways, and dense granule proteins can therefore join rhoptry proteins in T. gondii’s host cell–modifying arsenal. American Heart Association (Scientist Development Grant 0835099N) Massachusetts Life Sciences Center Singapore. Agency for Science, Technology and Research National Institutes of Health (U.S.) (AI080621) Cleo and Paul Schimmel Foundation Cancer Research Institute (New York, N.Y.) 2011-08-26T20:12:55Z 2011-08-26T20:12:55Z 2011-01 2010-04 Article http://purl.org/eprint/type/JournalArticle 0022-1007 1540-9538 http://hdl.handle.net/1721.1/65419 Rosowski, E. E. et al. “Strain-specific Activation of the NF- B Pathway by GRA15, a Novel Toxoplasma Gondii Dense Granule Protein.” Journal of Experimental Medicine 208.1 (2011) : 195-212. en_US http://dx.doi.org/10.1084/jem.20100717 Journal of Experimental Medicine Creative Commons Attribution-Non-Commercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Rockefeller University Press Rockefeller |
| spellingShingle | Rosowski, Emily Elizabeth Lu, Diana Julien, Lindsay Rodda, Lauren B. Gaiser, Rogier A. Saeij, Jeroen Jensen, Kirk D. Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title | Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title_full | Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title_fullStr | Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title_full_unstemmed | Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title_short | Strain-specific activation of the NF-kappa B pathway by GRA15, a novel Toxoplasma gondii dense granule protein |
| title_sort | strain specific activation of the nf kappa b pathway by gra15 a novel toxoplasma gondii dense granule protein |
| url | http://hdl.handle.net/1721.1/65419 |
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