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Effects of purinergic signaling in the mechanism involved in the hepatic necrosis induced by infection with Plasmodium chabaudi AS

Grant number: 12/02572-9
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Maria Regina D'Império Lima
Grantee:Flavia Sarmento Vieira
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Introduction: The intense activation of the immune system during the erythrocytic cycle of Plasmodium is responsible for several syndromes associated with the disease, such as anemia, cerebral malaria, metabolic acidosis and systemic shock. Some molecules released by damaged cells, such as ATP and uric acid, are detected by cells of the immune system. These damage signals participate in the activation of immune system but also promote the regulation of inflammation after trauma or injury caused by pathogens. Purinergic receptors of the P2X (P2X1-7R) family on the surface of immune cells detect extracellular ATP (eATP). The binding of eATP to P2X7R induces inflammasome activation in macrophages and consequent production of proinflammatory cytokines and cell death. In malaria, ATP is released upon erythrocyte rupture and T cell activation. In the murine model of malaria caused by Plasmodium chabaudi AS, erythrocytes infected with mature forms preferentially adhere in vessel endothelium of the liver. Therefore, it is believed that the rupture of parasitized erythrocytes and consequent release of ATP mainly occur in that organ. Corroborating this hypothesis, a study performed by our research group showed that the liver necrosis observed in infected C57BL/6 mice did not occur in mice deficient in P2X7R.Statement of problem: Little is known about the involvement of purinergic signaling in the hepatic necrosis caused by P. chabaudi AS infection.Experimental strategy: Five complementary approaches will be used to clarify this issue in the experimental model of acute and chronic malaria by P. chabaudi AS: 1) To quantify the expression of P2X7R in hepatocytes and Kupffer cells during infection. 2) To analyze the response of hepatocytes and Kupffer cells to ATP during infection, using specific inhibitors and mice deficient in P2X7R (P2X7R-/-). 3) To evaluate necrosis in chimeric mice with P2X7R+/+ hepatocytes and P2X7R-/- Kupffer cells, and vice-versa. 4) To analyze necrosis in mice deficient for other molecules involved in the inflammasome. 5) To evaluate whether there is hepatic necrosis during infection using a clone of the parasite that does not adhere to liver vessels (strain AJ).Expected results: To determine the role of P2X7R in the hepatic necrosis observed during the development of malaria caused by P. chabaudi AS.Expected contribution to the field: To provide the theoretical framework aiming to assess the possibility of using drugs that specifically inhibit the purinergic receptor P2X7, in order to confer protection against the disease symptoms resulting from the exaggerated immune response to Plasmodium infection.

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