Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>

ABSTRACT 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) inflammaso...

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Autores principales:	Gezahegn Gorfu, Kimberly M. Cirelli, Mariane B. Melo, Katrin Mayer-Barber, Devorah Crown, Beverly H. Koller, Seth Masters, Alan Sher, Stephen H. Leppla, Mahtab Moayeri, Jeroen P. J. Saeij, Michael E. Grigg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e46b702f63e4b6498962218d8a787d3
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spelling	oai:doaj.org-article:0e46b702f63e4b6498962218d8a787d32021-11-15T15:45:10ZDual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>10.1128/mBio.01117-132150-7511https://doaj.org/article/0e46b702f63e4b6498962218d8a787d32014-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01117-13https://doaj.org/toc/2150-7511ABSTRACT 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.Gezahegn GorfuKimberly M. CirelliMariane B. MeloKatrin Mayer-BarberDevorah CrownBeverly H. KollerSeth MastersAlan SherStephen H. LepplaMahtab MoayeriJeroen P. J. SaeijMichael E. GriggAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 1 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Gezahegn Gorfu Kimberly M. Cirelli Mariane B. Melo Katrin Mayer-Barber Devorah Crown Beverly H. Koller Seth Masters Alan Sher Stephen H. Leppla Mahtab Moayeri Jeroen P. J. Saeij Michael E. Grigg Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
description	ABSTRACT 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.
format	article
author	Gezahegn Gorfu Kimberly M. Cirelli Mariane B. Melo Katrin Mayer-Barber Devorah Crown Beverly H. Koller Seth Masters Alan Sher Stephen H. Leppla Mahtab Moayeri Jeroen P. J. Saeij Michael E. Grigg
author_facet	Gezahegn Gorfu Kimberly M. Cirelli Mariane B. Melo Katrin Mayer-Barber Devorah Crown Beverly H. Koller Seth Masters Alan Sher Stephen H. Leppla Mahtab Moayeri Jeroen P. J. Saeij Michael E. Grigg
author_sort	Gezahegn Gorfu
title	Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_short	Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_full	Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_fullStr	Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_full_unstemmed	Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>
title_sort	dual role for inflammasome sensors nlrp1 and nlrp3 in murine resistance to <named-content content-type="genus-species">toxoplasma gondii</named-content>
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/0e46b702f63e4b6498962218d8a787d3
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Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to <named-content content-type="genus-species">Toxoplasma gondii</named-content>

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