Reactive Astrocyte‐Associated IL‐33 Signaling Contributes to a Protective Neuroimmune State During Chronic Toxoplasma gondii – Plasmodium berghei Coinfection

ABSTRACT Cerebral malaria (CM) is a lethal neuroinflammatory syndrome characterized by blood–brain barrier disruption and excessive immune‐mediated neuronal damage. Astrocytes are emerging as key regulators of CNS homeostasis, yet their contribution to disease tolerance during polymicrobial infections remains poorly understood. Here, we show that chronic Toxoplasma gondii ( Tg ) infection protects against experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA ( Pb A) by establishing a regulated neuroimmune environment rather than reducing cerebral parasite burden. This protective phenotype required chronic cerebral T. gondii infection and was associated with a distinct neuroinflammatory transcriptional profile characterized by enhanced TGF‐β and IL‐33/ST2 expression. At the cellular level, chronic Tg infection remodeled the astrocyte compartment, generating reactive astrocytes displaying an intermediate inflammatory phenotype characterized by the co‐expression of inflammatory (CXCL‐10, MHC‐I) and regulatory (TGF‐β) markers. Reactive astrocytes represented one of the major IL‐33‐expressing cell populations in the brains of Tg ‐infected and coinfected mice and were associated with recruitment of ST2‐expressing group 2 innate lymphoid cells (ILC2s), which expressed IL‐5 and IL‐13 in the brain. In IL‐33‐deficient mice, cerebral ILC2 recruitment was markedly reduced and protection against ECM was only partially maintained, indicating that the IL‐33/ST2 axis contributes to, but is not solely responsible for, disease tolerance during coinfection. Our findings identify reactive astrocytes as key components of a regulated neuroimmune environment associated with protection against ECM during chronic T. gondii coinfection. These results highlight astrocyte‐associated IL‐33/ST2 signaling and ILC2 recruitment as components of a multicellular neuroimmune network that contribute to disease tolerance during polymicrobial CNS infections.