Regulation of Signaling through Extracellular ATP in Malaria-Associated Encephalopathy and Its Neurological Sequelae: Strategies to Prevent Damage Induced by Pathogenic T Lymphocytes

• Grant number: 25/05135-9
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Rodrigo Jose Rocha Xavier Freitas
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Extracellular ATP (eATP) is a key signaling molecule in the immune response to cellular damage, playing a central role in activating inflammatory and resident cells of the central nervous system. In malaria, particularly in severe cases such as cerebral malaria, ATP is released in large quantities due to cellular activation and death, inducing immune system activation and regulation through purinergic receptor engagement. Panexin-1 channels, which are upregulated in activated or dying cells, serve as major pathways for ATP release, thereby enhancing the activation of these receptors. Purinergic signaling mediated by eATP involves the P2X7 receptor, a crucial ion channel for immune and non-immune cell activation and effector functions. On the other hand, the ectonucleotidase CD39 hydrolyzes eATP, generating adenosine as a product and modulating inflammatory processes. Encephalopathy associated with cerebral malaria results from complex mechanisms, including endothelial cell activation and the accumulation of CD4+ and CD8+ T lymphocytes in the brain microvasculature. CD4+ Th1 T cells secrete IFN-¿, activating CD8+ T cells, which migrate to the brain, compromise the integrity of the blood-brain barrier, and increase its permeability. This allows the influx of cells and inflammatory mediators, intensifying astrocyte and microglia reactivity, ultimately contributing to synaptic dysfunction and neuronal death. Beyond acute encephalopathy, cerebral malaria is linked to long-term cognitive and behavioral sequelae, including memory deficits, anxiety, and depression-like behavior. In this context, the hypothesis of this study is that dysregulated eATP signaling contributes to cerebral malaria immunopathology and that modulating this pathway-through Panexin-1 channel inhibition and ATP degradation by ectonucleotidases-could mitigate disease pathology and prevent associated cognitive impairments. Thus, the aim of this project is to investigate the role of CD39 ectonucleotidase and Panexin-1 channels in regulating eATP signaling in cerebral malaria and its associated cognitive alterations, as well as to modulate this signaling pathway for therapeutic purposes. To achieve this, we will assess neuropathology in CD39-deficient mice and investigate the effects of pharmacological inhibition of Panexin-1 channels and eATP degradation. Our goal is to understand both the mechanisms involved in the acute phase of the disease and its associated neurological sequelae, as well as to identify potential therapeutic targets for cerebral malaria.