Abstract Toxoplasma gondii is an obligate intracellular pathogen that can infect most nucleated cell types in rodents and humans. Parasite infection is regulated by inflammasome activation, downstream of Toll-like receptors (TLRs) priming, and interferon γ (IFN-γ)-mediated activation of immunity inducible GTPases. In vivo, the activation of these pathways overlaps, however, the molecular mechanism of cooperation between IFN-γ signaling and inflammasome activation has not been rigorously explored during T. gondii infection. Here we show that IFN-γ is sufficient to prime T. gondii-induced inflammasome activation in murine myeloid cells. The cytosolic DNA sensor absent in melanoma 2 (AIM2) inflammasome plays a dominant role in IL-1β release through caspase-1/11 and ASC in cooperation with NLRP3. Unexpectedly, we found that AIM2 inflammasome activation was not dependent on parasite killing as iNOS-deficiency rescued T. gondii clearance but did not inhibit IL-1β release or cell death. Instead, we found that depleting host mitochondrial DNA (mtDNA) blocked IL-1β release, suggesting that host DNA is the ligand for AIM2. Moreover, we found that expressing mitochondrial association factor 1 (MAF1I) from the hyper-virulent type I strain in type II T. gondii significantly inhibited the release of mtDNA into the host cell cytosol and reduced inflammasome activation. These data indicate that T. gondii infection in the context of IFN-γ signaling leads to AIM2 inflammasome activation by host mtDNA, a process that is competitively inhibited by MAF1I-mediated mitochondrial recruitment to the parasitophorous vacuole.
Zhao et al. (Sun,) studied this question.