Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii
Top Cited Papers
Open Access
- 28 February 2014
- journal article
- Published by American Society for Microbiology in mBio
- Vol. 5 (1)
- https://doi.org/10.1128/mbio.01117-13
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. 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.Keywords
This publication has 67 references indexed in Scilit:
- Toxoplasma gondii effectors are master regulators of the inflammatory responseTrends in Parasitology, 2011
- Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificityNature, 2011
- The IRG protein-based resistance mechanism in mice and its relation to virulence in Toxoplasma gondiiCurrent Opinion in Microbiology, 2011
- Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal InflammationCell Host & Microbe, 2011
- Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine ProcessingCell Host & Microbe, 2010
- Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteriaNature Immunology, 2010
- The immunity-related GTPases in mammals: a fast-evolving cell-autonomous resistance system against intracellular pathogensMammalian Genome, 2010
- Evidence for associations between the purinergic receptor P2X7 (P2RX7) and toxoplasmosisGenes & Immunity, 2010
- Gr1+ Inflammatory Monocytes Are Required for Mucosal Resistance to the Pathogen Toxoplasma gondiiImmunity, 2008
- Toxoplasma gondii: Induction of egress by the potassium ionophore nigericinInternational Journal for Parasitology, 2007