Scholarship 23/10839-0 - Malária, Plasmodium berghei - BV FAPESP
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Effects of CD39 ectonucleotidase and purinergic receptors in experimental Pulmonary Malaria

Grant number: 23/10839-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Start date until: December 01, 2023
End date until: November 30, 2026
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Maria Regina D'Império Lima
Grantee:Luciana dos Santos Barros Manhães
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/20432-8 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis, AP.TEM

Abstract

Acute respiratory distress syndrome (ARDS) associated with malaria is due to an intense inflammatory response in the lungs. Granzymes and perforins released by parasite-specific CD8+ T cells disrupt the alveolar-capillary barrier, resulting in fluid leakage into the lung interstitial space and, consequently, hypoxia. In this context, there is release of adenosine triphosphate molecules into the extracellular environment (eATP), which may contribute to the acute inflammatory process through the signaling of purinergic P2 receptors. eATP is phosphohydrolyzed by ectonucleotidase CD39, expressed in lung cells, such as immune and endothelial cells, generating adenosine (ADO), which negatively regulates the immune response by acting on purinergic P1 receptors. Thus, we postulate that CD39 may have a modulating effect on lung disease resulting from malaria, and that P2RX7, P2RY6 and P2Y12 receptors may influence the course of the pathology. Thus, wild-type C57BL/6 mice and mice deficient in CD39 and P2X7 (Entpd1-/- and P2RX7-/-) infected with Plasmodium berghei (strain NK65) will be monitored in relation to clinical and respiratory parameters, as well as histological and leukocyte composition analyses. pulmonary. If there are differences between the animals, the role of CD39 and P2X7 in CD8+ T lymphocytes will be investigated in CD8-/- mice transferred with cells that do or do not express these molecules. In addition, we will use P2X7, P2RY6 and P2RY12 receptor inhibitors to treat infected mice. We emphasize that the pathogenesis of pulmonary malaria and its immunological mechanisms need to be understood in detail in order to contribute to the development of target-specific therapies. (AU)

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