The inflammatory role of host mitochondrial DNA release during Toxoplasma gondii infection of murine immune cells 73 views

Toxoplasma gondii is a globally prevalent intracellular parasite capable of establishing lifelong infection, controlled primarily through interferon-γ (IFNγ)–driven cell-autonomous immunity, inflammasome activation, and sustained T-cell responses. While IFNγ-inducible guanylate-binding proteins (GBPs) and immunity-related GTPases target the parasitophorous vacuole for clearance, the molecular mechanisms linking IFNγ priming to inflammasome activation in murine immune cells have remained unclear. Here, we identify a central role for host mitochondrial DNA (mtDNA) release in coordinating innate immune signaling during T. gondii infection. We show that IFNγ and TLR2 priming are sufficient to upregulate inflammasome components and cause mtDNA release in murine myeloid cells, but IFNγ and TLR2 and T. gondii infection trigger inflammasome activation. Absent in Melanoma 2 (AIM2) was found as the dominant sensor driving IL-1β release through caspase-1/11 and apoptosis-associated speck-like protein containing a CARD (ASC), in cooperation with NOD-like receptor family pyrin domain containing 3 (NLRP3). Depletion of host mtDNA abrogated IL-1β secretion, demonstrating that mtDNA is the principal ligand for AIM2 in this context. Notably, inflammasome activation occurred independently of parasite killing, as iNOS deficiency rescued parasite clearance yet did not impair IL-1β production or cell death. We further reveal that the type I T. gondii mitochondrial association factor MAF1I suppresses mtDNA release and inflammasome activation by enhancing host mitochondrial recruitment to the parasitophorous vacuole. Together, these findings define a mechanistic link between IFNγ and NF-κB priming, mitochondrial dynamics, and AIM2-dependent sensing of host mtDNA during T. gondii infection, providing new insight into host-parasite interactions that govern inflammation, parasite control, and chronic cyst persistence.

PHD (Doctor of Philosophy)

Toxoplasma gondii ; AIM2 inflammasome ; Mitochondria DNA release

English

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2025-12-05