Effects of CD39 ectonucleotidase and purinergic receptors on experimental pulmonary malaria

Acute respiratory distress syndrome (ARDS) associated with malaria occurs due to an intense inflammatory response in the lungs. Granzymes and perforins released by parasite-specific CD8+ T cells disrupt the alveolar-capillary barrier, which results in fluid leakage into the interstitial space of the lung and, consequently, hypoxia. In this context, there is a release of adenosine triphosphate molecules into the extracellular environment (eATP), which can contribute to the acute inflammatory process through signaling from P2 purinergic receptors. eATP is phosphohydrolyzed by the ectonucleotidase CD39, expressed in lung cells, such as immune and endothelial cells, generating adenosine (ADO), which negatively regulates the immune response by acting on P1 purinergic receptors. Therefore, we postulate that CD39 may have a modulatory effect on lung disease resulting from malaria, and that P2RX7, P2RY6 and P2Y12 receptors may influence the course of the pathology. Thus, C57BL/6 wild-type mice and those 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. If there are differences between 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. Furthermore, we will use inhibitors of the P2X7, P2RY6 and P2RY12 receptors to treat infected mice. It is emphasized 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.

Project details

Basic Science

Dec 2023 — Nov 2026

Brazil