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Purinergic signaling in the pathogenesis of acute lung injury and acute respiratory distress syndrome associated with pulmonary malaria

Grant number: 20/09043-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2020
Effective date (End): October 31, 2021
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Maria Regina D'Império Lima
Grantee:Caio César Barbosa Bomfim
Home 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

Malaria is an infectious disease caused by a microorganisms of the genus Plasmodium. It is still considered a public health problem, exposing many populations around the world at risk, especially those who live in tropical and subtropical areas. The role of P2X7 receptor (P2X7R) on the pathogenesis of experimental malaria has been greatly explored by our laboratory. In the malaria blood-stage induced by Plasmodium chabaudi, the P2X7R signaling displayed key role in the activation and polarization to Th1 lymphocytes and increase of IFN-y production, which was accompanied by a reduction of parasitemia and decrease of disease symptoms. However, in some severe cases of malaria, the pulmonary complications can lead to Acute Respiratory distress Syndrome (ARDS), caused by enhance of vascular permeability and lung edema with consequently hypoxemia. It has been reported that low levels of oxygen induces increase of P2X7R expression in some cells. In addition, the P2X7R are also related to metabolism shifting from oxidative phosphorylation to glycolysis in nutrients scarce environment or when there is a requirement for fast energy source, as during lymphocyte proliferation. Considering a context where the oxygen supply is compromised, shifting the way to obtaining energy becomes essential for the cell survival, because oxidative respiration is progressively reduced as the oxygen tension decreases. However, P2X7R activation with high ATP concentrations during long period can cause pore formation in the plasma membrane leading to cell death. In addition, P2X7R can also activate ADAM17, which cleaves CD62L and favors the lymphocyte migration to tissues. CD8+ T lymphocytes are described as one of the main cells that promote lung malaria, while monocytes/macrophages are related to removal of parasitized erythrocytes and reduction of lung pathology. We wonder whether high levels of P2X7R expression induced by hypoxemia, can facilitate lung malaria aggravation by increase survival of CD8+ T lymphocytes in the lung, and/or by induce monocyte death. Thus, the aims of this study is to evaluate the importance of P2X7R activation in CD8+ T lymphocytes and monocytes in a hypoxia condition during ALI/ARDS associated with malaria, as well as CD39 ectonucleotidase, responsible for ATP degradation.In addition, its is know that lung malaria display several similarities to the acute respiratory syndrome associated with SARS-CoV2 infection, such as diffuse pulmonary edema and accumulation of inflammatory cells in the interstitial and alveolar spaces, including neutrophils, which can lead to death. Due to the current pandemic and the urgency to understand the pathogenesis of Covid-19, we have extended our aims to study the effects of P2X7 receptor inhibitors and the ketogenic diet on the experimental model of COVID-19 in hamsters. (AU)