Effect of CD39 ectonucleotidase on the immunopathology of cerebral malaria and its role in the infiltration of CD8 T lymphocytes in the central nervous system

• Grant number: 23/07938-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2023
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular 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
• 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

Cerebral malaria is characterized by proliferation of Th1-profile CD4+ T cells and CD8+ T cells (CTLs) in the spleen, which migrate to the cerebral microvasculture, promoting dysfunction of the blood-brain barrier (BBB). In the parenchyma, CTLs and Th1 cells contribute to the reactivity of glial cells, inducing neuroinflammation, promoting cell death and increasing levels of extracellular ATP (eATP). eATP exerts a danger signal and induces inflammation. In this context, the ENTPDases CD39 and CD73 are responsible for the cleavage of eATP into adenosine, a molecule with immunomodulatory and neuroprotective capacity. The present work postulates that CD39 ectonucleotidase can reduce the levels of eATP released during cell damage and neuroinflammation, degrading this molecule and generating adenosine, with neuroprotective and anti-inflammatory capacity. Therefore, this project aims to analyze the effect of CD39 ectonucleotidase on the immunopathology of cerebral malaria mediated by CD8+ T lymphocytes, as well as its role in neuroinflammation. For this, the experimental model of cerebral malaria will be used from the infection of mice C57BL6 and ENTPD1-/- with Plasmodium berghei ANKA. In order to evaluate the role of CD39 in CD8+ T lymphocytes, CD8-/- mice will be adoptively transferred with these cells devoid or not of CD39. Parasites of survival and parasitemia will be evaluated, as well as histological analysis of the spleen and brain, analysis of neuroinflammation, from immunostaining and phenotyping of glial cells, and lymphocytic infiltrate in the brain.