ZBP1 mediated restriction of Toxoplasma gondii in both the early acute and chronic brain stages of infection.

Abstract

ZBP1 is an innate sensor of nucleic acids in the Z-conformation and regulates immune responses via cell death pathways and nuclear factor κB signaling. Previous work has demonstrated an essential role for ZBP1 in viral restriction; however, the role ZBP1 plays in protection against other pathogens is in early stages of exploration. Toxoplasma gondii is an obligate intracellular parasite that can infect all nucleated cells and establishes a chronic infection of the brain requiring a robust innate and adaptive immune response and multiple cell death pathways for host survival. Importantly, innate sensors of T. gondii infection of the central nervous system are still being defined. Prior work has implicated caspase-1 and caspase-8 in the control of T. gondii in the brain. Because ZBP1 can activate both caspase-1 and caspase-8, we sought to explore the role of ZBP1 during T. gondii infection. During early infection, we found an increase in parasite burden; a decrease in NK1.1+ cell, neutrophil, and monocyte recruitment; and impaired NK1.1+ cell cytokine production in the peritoneum of Zbp1-/- mice. Interestingly, during the early adaptive immune response, the immune cell recruitment defects and impaired parasite control were ameliorated. During the brain stage of infection, ZBP1 regulated parasite restriction and numerous inflammatory responses to infection. Our findings establish ZBP1 as a critical regulator of host defense to T. gondii and highlight the importance of ZBP1 in development of inflammation during both the acute and chronic infection.