Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii

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 Saeij, Michael E. Grigg

Research output: Contribution to journalArticle

111 Scopus citations

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.

Original languageEnglish (US)
Article numbere01117-13
JournalmBio
Volume5
Issue number1
DOIs
StatePublished - Feb 18 2014
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Virology

Fingerprint Dive into the research topics of 'Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii'. Together they form a unique fingerprint.

  • Cite this

    Gorfu, G., Cirelli, K. M., Melo, M. B., Mayer-Barber, K., Crown, D., Koller, B. H., Masters, S., Sher, A., Leppla, S. H., Moayeri, M., Saeij, J., & Grigg, M. E. (2014). Dual role for inflammasome sensors NLRP1 and NLRP3 in murine resistance to Toxoplasma gondii. mBio, 5(1), [e01117-13]. https://doi.org/10.1128/mBio.01117-13