RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection

Abstract

<i>Toxoplasma gondii</i> infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a proinflammatory cell death pathway apart from the innate immune response that has evolved to control pathogenic infection. In this study, we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to <i>T. gondii</i> infection. We found that ZBP1 does not induce proinflammatory necroptosis cell death, and ZBP1 null mice have reduced survival after oral <i>T. gondii</i> infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3^-/-), a central mediator of necroptosis, have significantly improved survival after oral <i>T. gondii</i> infection without a reduction in parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villus immunopathology, but RIPK3^-/- mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed-lineage kinase domain-like pseudokinase null (MLKL^-/-) mice. We found MLKL^-/- mice succumbed to oral <i>T. gondii</i> infection the same as wild-type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of proinflammatory cell death pathways as a mechanism of host defense to oral <i>T. gondii</i> infection.