Astrocytes promote a protective immune response to brain Toxoplasma gondii infection via IL-33-ST2 signaling

Understanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-{gamma}-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.