Astrocytes control the Neuroinflammation and ILC2 response through IL-33/ST2 signaling, during protection against Cerebral Malaria in Toxoplasma-P. berghei coinfected Mice

Abstract

Cerebral malaria (CM) is a complex multi-systemic disorder defined as a diffuse encephalopathy with acute neurological manifestations characterized by alterations in the level of consciousness, deep coma and seizure preceding death. During infection, astrocytes undergo significant morphological and molecular changes, adopting a reactive state that impacts on their functions. This reactivity is characterized by a shift in from a neuroprotective (A2) to a neurotoxic (A1) phenotype, influencing the outcome of the immune response. These phenotypes may vary depending on the chronicity of the infection or multiples infections of the same host. In this study, we investigated how Toxoplasma gondii (Tg) brain infection impacts on the outcome of experimental cerebral malaria (ECM) in mice infected with Plasmodium berghei ANKA (PbA). Our results highlighted an immunomodulatory role of GFAP+ astrocytes underweening significant morphological and molecular alterations and adopting a unique intermediate reactivity state (A1/A2). This state was correlated with production of CXCL-10 and TGF-{beta}, which control inflammation without exacerbating infection. Our study also revealed a key role of the IL-33/ST2 pathway induced by Tg brain infection in protecting against ECM. Astrocyte-derived IL-33 was crucial to promote brain recruitment and activation of innate lymphoid cells (ILC2), which contribute to the hosts antiparasitic response. Additionally, we identified a distinctive intermediate M1/M2 phenotype in CD86+CD206+CD16/32+MHCIIhi microglia and noted an enhanced recruitment of inflammatory monocytes, both contributing to inflammation and control of PbA infection. This study reveals, for the first time, how latent brain infection with T. gondii confers protection against a severe cerebral form of malaria, positioning astrocytes at the core of the neuroinflammatory response that controls PbA infection severity. This expands our understanding of host-pathogen interactions and the potential for targeting astrocytic pathways in preventing CM. Author SummaryCerebral malaria (CM) is one of the most severe complications of Plasmodium infection, often leading to coma and death. The mechanisms that determine why some individuals develop this life-threatening condition remain poorly understood. In this study, we explored how a chronic brain infection with the parasite Toxoplasma gondii influences the development of CM in mice. We found that Tg infection reshapes the brains immune environment, particularly through the actions of astrocytes, cells that normally support and protect neurons. During coinfection, astrocytes adopted a balanced reactive state that limited inflammation without worsening the infection. This response involved the IL-33/ST2 signalling pathway and led to the recruitment of protective immune cells, helping to control Plasmodium infection in the brain. Our findings uncover an unexpected protective role of latent T. gondii infection and identify astrocytes as central regulators of neuroinflammation. This work highlights potential new strategies for preventing or mitigating cerebral malaria by targeting astrocyte-mediated immune responses.