Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii
Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensor...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Society for Microbiology
2014
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| Online Access: | http://hdl.handle.net/1721.1/89662 https://orcid.org/0000-0003-4583-1118 |
| _version_ | 1811091329301610496 |
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| author | Gorfu, Gezahegn Cirelli, Kimberly Melo, Mariane Bandeira Mayer-Barber, Katrin Crown, Devorah Koller, Beverly H. Masters, Seth Sher, Alan Leppla, Stephen H. Moayeri, Mahtab Saeij, Jeroen Grigg, Michael E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Gorfu, Gezahegn Cirelli, Kimberly Melo, Mariane Bandeira Mayer-Barber, Katrin Crown, Devorah Koller, Beverly H. Masters, Seth Sher, Alan Leppla, Stephen H. Moayeri, Mahtab Saeij, Jeroen Grigg, Michael E. |
| author_sort | Gorfu, Gezahegn |
| collection | MIT |
| description | Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1β (IL-1β), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1β in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis.
IMPORTANCE Inflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain “sensor” proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival. |
| first_indexed | 2024-09-23T15:00:44Z |
| format | Article |
| id | mit-1721.1/89662 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:00:44Z |
| publishDate | 2014 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | mit-1721.1/896622022-09-29T12:02:22Z Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii Gorfu, Gezahegn Cirelli, Kimberly Melo, Mariane Bandeira Mayer-Barber, Katrin Crown, Devorah Koller, Beverly H. Masters, Seth Sher, Alan Leppla, Stephen H. Moayeri, Mahtab Saeij, Jeroen Grigg, Michael E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Melo, Mariane Bandeira Cirelli, Kimberly Saeij, Jeroen Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1β (IL-1β), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1β in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. IMPORTANCE Inflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain “sensor” proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival. National Institutes of Health (U.S.) (Intramural Research Program of the NIH and NIAID) Crohn's and Colitis Foundation of America (Research Fellowship) Crohn's and Colitis Foundation of America (CCFA Helmsley Scholar) National Institutes of Health (U.S.) (NIH grant AI104170) National Institutes of Health (U.S.) (R01-AI080621) Pew Charitable Trusts (Pew Scholars Program in the Biomedical Sciences) Canadian Institute for Advanced Research (CIFAR Program for Integrated Microbial Biodiversity) 2014-09-16T20:25:14Z 2014-09-16T20:25:14Z 2014-02 2013-12 Article http://purl.org/eprint/type/JournalArticle 2150-7511 http://hdl.handle.net/1721.1/89662 Gorfu, G., K. M. Cirelli, M. B. Melo, K. Mayer-Barber, D. Crown, B. H. Koller, S. Masters, et al. “Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma Gondii.” mBio 5, no. 1 (December 31, 2013): e01117–13–e01117–13. https://orcid.org/0000-0003-4583-1118 en_US http://dx.doi.org/10.1128/mBio.01117-13 mBio Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/3.0 application/pdf American Society for Microbiology American Society for Microbiology |
| spellingShingle | Gorfu, Gezahegn Cirelli, Kimberly Melo, Mariane Bandeira Mayer-Barber, Katrin Crown, Devorah Koller, Beverly H. Masters, Seth Sher, Alan Leppla, Stephen H. Moayeri, Mahtab Saeij, Jeroen Grigg, Michael E. Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title | Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title_full | Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title_fullStr | Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title_full_unstemmed | Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title_short | Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii |
| title_sort | dual role for inflammasome sensors nlrp1 and nlrp3 in murine resistance to toxoplasma gondii |
| url | http://hdl.handle.net/1721.1/89662 https://orcid.org/0000-0003-4583-1118 |
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