Effects of purinergic signaling in the immune response and pathogenesis during Plasmodium chabaudi AS malaria

• Grant number: 11/24038-1
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2012
• End date: March 31, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Maria Regina D'Império Lima
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

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 inflamossoma activation in macrophages and consequent production of proinflammatory cytokines and cell death. The P2X1R and P2X4R are located at immune synapses and contribute to T cell activation. On the other hand, regulatory T cells (Treg) have ecto-ATPases on the surface that cleave eATP and thus regulate the immune system. In malaria, ATP is released upon erythrocyte rupture and T cell activation. Statement of problem: Little is known about the involvement of purinergic signaling in the pathogenesis and development of immune response during malaria. Experimental strategy: The project is divided into five parts with complementary approaches aiming to clarify this problem in the experimental model of acute and chronic malaria by P. chabaudi AS: 1) To quantify the expression of purinergic receptors in the spleen, liver, kidneys and lungs. 2) To analyze in vitro the involvement of purinergic signaling in the activation and death of immune cells induced by infection, using specific inhibitors and mice deficient in P2X7R (P2X7R-/-). 3) To evaluate the role of purinergic receptors on the activity of splenic Treg cells. 4) To determine the effects of in vivo inhibition of P2X receptors or P2X7R deficiency, in relation to clinical manifestations of the disease, development of immune response and protection. 5) To compare the immune response and the development of the disease in chimeric mice for bone marrow cells. Expected results: To determine which are the P2X receptors involved in the pathogenesis and immune response against malaria. Expected contribution to the field: To provide the theoretical framework to assess the possibility of using drugs that specifically inhibit the purinergic receptors involved in malaria, in order to confer protection against the disease symptoms resulting from the exaggerated immune response to Plasmodium infection. Existing support: This study is fully consistent with the work being developed by our research group with the support of FAPESP (scholarships for master and doctorate) and CNPq (productivity fellowship and Universal grant). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA SILVA, HENRIQUE BORGES; FONSECA, RAISSA; CASSADO, ALEXANDRA DOS ANJOS; DE SALLES, ERIKA MACHADO; DE MENEZES, MARIA NOGUEIRA; LANGHORNE, JEAN; PEREZ, KATIA REGINA; CUCCOVIA, IOLANDA MIDEA; RYFFEL, BERNHARD; BARRETO, VASCO M.; et al. In Vivo Approaches Reveal a Key Role for DCs in CD4+T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria. PLOS PATHOGENS, v. 11, n. 2, FEB 2015. (09/08559-1, 11/24038-1)

DA SILVA, HENRIQUE BORGES; DE SALLES, ERIKA MACHADO; PANATIERI, RAQUEL HOFFMANN; BOSCARDIN, SILVIA BEATRIZ; RODRIGUEZ-MALAGA, SERGIO MARCELO; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. IFN-gamma-Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria. JOURNAL OF IMMUNOLOGY, v. 191, n. 10, p. 5160-5169, NOV 15 2013. (09/08559-1, 11/24038-1)