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

Abstract

It is of great interest to understand how invading pathogens are sensed within the brain, a tissue with unique challenges to mounting an immune response. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts, and initiates robust immune cell recruitment, but little is known about pattern 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, like many other pattern recognition pathways, IL-33 can signal peripherally, and 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 locally 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 and/or maintenance of blood-derived anti-parasitic immune cells, including proliferating, IFN-γ-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-33 receptor-deficient astrocytes fail to mount an adequate adaptive immune response in the CNS to control parasite burden–demonstrating, genetically, that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released locally, and sensed locally, to engage the peripheral immune system in controlling a pathogen.

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

“…Neuroprotective and repair mechanisms in other non-infectious models of CNS injury include remyelination to increase conductivity between previously damaged neurons, synaptic pruning by microglia to limit over-signaling, regeneration of axons, and various others. Recent work by the Harris lab indicates a role for local release of the DAMP IL-33 either by oligodendrocytes or astrocytes that is then required for protection against Toxoplasma ( Still et al., 2020 ). Such innate sensing mechanisms may be needed not just for parasite recognition but also as a trigger to activate neural repair during late infection.…”

IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity toToxoplasma gondii

“…CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made required for control of T. gondii in the CNS [65]. Nevertheless, the data presented here establish that the ability of IL-33 to amplify ILC responses and their production of IFN-g plays a protective role in the acute innate response to Toxoplasma.…”

“…Indeed, during intracerebral LCMV infection IL-33 contributes to the development of lethal immune pathology [63], whereas for mice chronically infected with T. gondii the loss of IL-33 results in increased parasite burden [66]. More recent studies have highlighted that IL-33 promotes astrocyte responses that promote T cell responses 16 required for control of T. gondii in the CNS [65]. Nevertheless, the data presented here establish that the ability of IL-33 to amplify ILC responses and their production of IFN-g plays a protective role in the acute innate response to Toxoplasma.…”

“…However, during infection with LCMV or MCMV, IL-33 promotes the expansion of NK cells and T cells and their production of IFN-γ, and loss of the IL-33R results in a delay in viral clearance [62]–[64]. In contrast, perhaps one of the most strking phenotypes of mice that lack IL-33R is that they succumb to chronic toxoplasmosis, associated with reduced astrocyte responses required for protective T cell responses [65],[66]. Nevertheless, the acute stage of toxoplasmosis is associated with the ability of T. gondii to infect and lyse epithelial and endothelial cells [67]–[71], but whether these events lead to the release of IL-33 or if this affects the innate response to Toxoplasma is unknown.…”

“…However, during infection with LCMV or MCMV, IL-33 promotes the expansion of NK cells and T cells and their production of IFNg, and loss of the IL-33R results in a delay in viral clearance [62]- [64]. In contrast, perhaps one of the most strking phenotypes of mice that lack IL-33R is that they succumb to chronic toxoplasmosis, associated with reduced astrocyte responses required for protective T cell responses [65], [66].…”