Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii

<jats:title>ABSTRACT</jats:title><jats:p>Induction of immunity that limits<jats:named-content content-type="genus-species">Toxoplasma gondii</jats:named-content>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<jats:italic>in vitro Toxoplasma</jats:italic>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,<jats:italic>Toxoplasma</jats:italic>-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<jats:named-content content-type="genus-species">T. gondii</jats:named-content>as a novel activator of the NLRP1 and NLRP3 inflammasomes<jats:italic>in vivo</jats:italic>and establish a role for these sensors in host resistance to toxoplasmosis.</jats:p><jats:p><jats:bold>IMPORTANCE</jats:bold>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.<jats:named-content content-type="genus-species">Toxoplasma gondii</jats:named-content>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<jats:named-content content-type="genus-species">T. gondii</jats:named-content>is a novel activator of the NLRP1 and NLRP3 inflammasomes<jats:italic>in vivo</jats:italic>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.</jats:p>