Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis

• Grant number: 15/20432-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: December 01, 2016
• End date: November 30, 2024
• 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
• City of the host institution: São Paulo
• Principal investigators: José Maria Álvarez Mosig
• Principal investigators: Mario Hiroyuki Hirata
• Associated researchers: Alessandra Pontillo ; Cláudio Romero Farias Marinho ; Elena Lassounskaia ; Franklin Alan Sher ; Henrique Borges da Silva ; João Gustavo Pessini Amarante Mendes ; José Carlos Farias Alves Filho ; José Maria Álvarez Mosig ; Karina Ramalho Bortoluci ; Mario Hiroyuki Hirata ; Robson Coutinho Silva ; Sabrina Epiphanio
• Associated scholarship(s): 24/05893-8 - Study of the participation of purinergic receptors in the development of the immune response against experimental malaria, BP.PD; 23/15373-9 - Study of T cell-mediated immunity in experimental COVID-19: involvement of purinergic signaling, BP.DD; 23/10839-0 - Effects of CD39 ectonucleotidase and purinergic receptors in experimental Pulmonary Malaria, BP.DD; + associated scholarships 23/07938-6 - 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, BP.MS; 22/14529-2 - Evaluation of the role of IF1 on CD4+ T cell differentiation: possible regulatory action of P2X7 and CD39, BP.MS; 22/07800-1 - Study of T cell-mediated immunity in experimental COVID-19: involvement of purinergic signaling, BP.MS; 22/00858-4 - The role of CD39 ectonucleotidase in acute respiratory distress syndrome associated with pulmonary malaria, BP.MS; 22/02488-0 - Purinergic signaling in the pathogenesis of acute lung injury and acute respiratory distress syndrome associated with pulmonary malaria, BP.PD; 22/00794-6 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of Malaria and Tuberculosis, BP.PD; 20/09043-8 - Purinergic signaling in the pathogenesis of Acute Lung Injury and Acute Respiratory Distress Syndrome associated with pulmonary Malaria, BP.PD; 20/04183-6 - Evaluation of P2X7 influence on caspase-1 activation and GSDMD cleavage in Tfh and Tfr cells in experimental Malária model, BP.IC; 20/01197-6 - Role of P2X7 receptor and CD39 ectonucleotidase in follicular regulatory T lymphocytes during experimental Malaria, BP.DD; 19/24700-8 - Role of P2X7 receptor on parenchymal and intravascular CD4 T cell response in a Severe Experimental Tuberculosis model, BP.DD; 17/11030-9 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis, BP.PD; 17/03354-9 - Role of purinergic receptors in the immune response development against experimental malaria, BP.PD - associated scholarships

Abstract

Dead cells as a result of tissue damage are quickly engulfed, but before disappearing, warn the surrounding cells so that repair programs are activated. The recognition of cell damage by the innate immune system contributes to the development of inflammatory immune responses and tissue repair, but may also exacerbate tissue injuries. In some cases, uncontrolled cell death can trigger a cascade of destructive processes that ultimately amplifies tissue damage and worsens the disease prognosis. The aim of this project is to characterize the receptors of cellular damage signals that are involved in the progression of severe forms of experimental malaria and tuberculosis, seeking to interfere in these signaling pathways in order to improve disease outcomes. These infectious diseases are among the most prevalent in humans, and together account for more than one million deaths annually worldwide. Another purpose of this project is to evaluate the role of signs of damage in the development of acquired immune response during these infectious diseases. This study can bring an essential knowledge for the development of new therapeutic approaches that can be applied, in conjunction with those already used, in the treatment of severe forms of malaria and tuberculosis, as well as in other diseases (infectious or not) that are characterized by extensive tissue damage. In addition, this study may uncover new molecular mechanisms involved in the recognition of cellular damage and, therefore, increase the understanding and intervention perspectives related to these processes. (AU)

Scientific publications

(12)

(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)

FONSECA, RAISSA; SALGADO, RAFAEL MOYSES; DA SILVA, HENRIQUE BORGES; DO NASCIMENTO, ROGERIO SILVA; D'IMPERIO-LIMA, MARIA REGINA; ALVAREZ, JOSE MARIA. Programmed Cell Death Protein 1-PDL1 Interaction Prevents Heart Damage in Chronic Trypanosoma cruzi Infection. FRONTIERS IN IMMUNOLOGY, v. 9, MAY 7 2018. (15/20432-8, 13/08199-0, 14/03802-3)

DE MENEZES, MARIA NOGUEIRA; SALLES, ERIKA MACHADO; VIEIRA, FLAVIA; AMARAL, EDUARDO PINHEIRO; ZUZARTE-LUIS, VANESSA; CASSADO, ALEXANDRA; EPIPHANIO, SABRINA; ALVAREZ, JOSE MARIA; ALVES-FILHO, JOSE CARLOS; MOTA, MARIA MANUEL; et al. IL-1 alpha, promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria. SCIENTIFIC REPORTS, v. 9, MAY 20 2019. (15/20432-8, 13/09176-4, 13/07140-2, 15/25874-9)

DA SILVA, HENRIQUE BORGES; DE SALLES, ERIKA MACHADO; LIMA-MAURO, ELIANA FAQUIM; SARDINHA, LUIZ ROBERTO; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. CD28 deficiency leads to accumulation of germinal-center independent IgM(+) experienced B cells and to production of protective IgM during experimental malaria. PLoS One, v. 13, n. 8, AUG 27 2018. (10/51150-4, 15/20432-8, 09/08559-1, 13/07140-2)

SANTIAGO-CARVALHO, IGOR; ALMEIDA-SANTOS, GISLANE; MACEDO, BRUNA GOIS; BARBOSA-BOMFIM, CAIO CESAR; ALMEIDA, FABRICIO MOREIRA; CIONE, MARCOS VINICIOS PINHEIRO; VARDAM-KAUR, TRUPTI; MASUDA, MIA; VAN DIJK, SARAH; MELO, BRUNO MARCEL; et al. T cell-specific P2RX7 favors lung parenchymal CD4⁺ T cell accumulation in response to severe lung infections. CELL REPORTS, v. 42, n. 11, p. 22-pg., 2023-11-15. (19/24700-8, 15/20432-8)

SALLES, ERIKA MACHADO DE; RAEDER, PAULO LISBOA; ANGELI, CLAUDIA BLANES; SANTIAGO, VERONICA FEIJOLI; DE SOUZA, CRISTIANE NAFFAH; RAMALHO, THERESA; CAMARA, NIELS OLSEN SARAIVA; PALMISANO, GIUSEPPE; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis. FRONTIERS IN IMMUNOLOGY, v. 14, p. 12-pg., 2023-03-13. (17/03354-9, 15/20432-8)

HERNANDEZ-TORRES, MARCELA; DO NASCIMENTO, SILVA ROGERIO; REBOUCAS, MONICA CARDOZO; CASSADO, ALEXANDRA; MATTEUCCI, KELY CATARINE; D'IMPERIO-LIMA, MARIA REGINA; VASCONCELOS, JOSE RONNIE C.; BORTOLUCI, KARINA R.; ALVAREZ, JOSE MARIA; AMARANTE-MENDES, GUSTAVO P.. Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection (vol 12, 817, 2021). CELL DEATH & DISEASE, v. 12, n. 9, p. 1-pg., 2021-08-30. (15/20432-8, 15/09568-5, 18/15607-1, 17/25942-0, 18/25984-7, 16/24912-7, 12/24737-0)

DE SALLES, ERIKA MACHADO; DE MENEZES, MARIA NOGUEIRA; SIQUEIRA, RENAN; DA SILVA, HENRIQUE BORGES; AMARAL, EDUARDO PINHEIRO; CASTILLO-MENDEZ, SHEYLA INES; CUNHA, ISABELA; CASSADO, ALEXANDRA DOS ANJOS; VIEIRA, FLAVIA SARMENTO; NICHOLAS OLIVIERI, DAVID; et al. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria. PLOS PATHOGENS, v. 13, n. 8, AUG 2017. (10/51150-4, 15/20432-8, 11/11053-2, 13/07140-2)

AMARAL, EDUARDO P.; DE SALLES, ERIKA MACHADO; BARBOSA BOMFIM, CAIO CESAR; SALGADO, RAFAEL MOYSES; ALMEIDA, FABRICIO M.; DE SOUZA, PAULA CAROLINA; ALVAREZ, JOSE MARIA; HIRATA, MARIO H.; LASUNSKAIA, ELENA B.; D'IMPERIO-LIMA, MARIA REGINA. Inhibiting Adenosine Receptor Signaling Promotes Accumulation of Effector CD4(+) T Cells in the Lung Parenchyma During Severe Tuberculosis. Journal of Infectious Diseases, v. 219, n. 6, p. 964-974, MAR 15 2019. (15/20432-8)

BARBOSA BOMFIM, CAIO CESAR; AMARAL, EDUARDO PINHEIRO; CASSADO, ALEXANDRA DOS ANJOS; SALLES, ERIKA MACHADO; DO NASCIMENTO, ROGERIO SILVA; LASUNSKAIA, ELENA; HIRATA, MARIO HIROYUKI; ALVAREZ, JOSE MARIA; D'IMPERIO-LIMA, MARIA REGINA. P2X7 receptor in Bone Marrow-Derived cells aggravates Tuberculosis caused by hypervirulent Mycobacterium bovis. FRONTIERS IN IMMUNOLOGY, v. 8, APR 13 2017. (12/22587-0, 14/22986-8, 15/20432-8, 13/07140-2)

SANTIAGO-CARVALHO, IGOR; DE ALMEIDA-SANTOS, GISLANE; BARBOSA BOMFIM, CAIO CESAR; DE SOUZA, PAULA CAROLINA; SANTOS E SILVA, JUAN CARLO; SILVA DE MELO, BRUNO MARCEL; AMARAL, EDUARDO PINHEIRO; PINHEIRO CIONE, MARCOS VINICIOS; LASUNSKAIA, ELENA; HIRATA, MARIO HIROYUKI; et al. P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, MAY 5 2021. (19/24700-8, 19/27139-5, 20/09043-8, 17/11030-9, 15/20432-8)

BARBOSA BOMFIM, CAIO CESAR; AMARAL, EDUARDO PINHEIRO; SANTIAGO-CARVALHO, IGOR; SANTOS, GISLANE ALMEIDA; SALLES, ERIKA MACHADO; HASTREITER, ARACELI APARECIDA; DO NASCIMENTO, ROGERIO SILVA; ALMEIDA, FABRICIO M.; BIA VENTURA SIMAO, THATIANA LOPES; REZENDE, ANDREZA LINHARES; et al. Harmful Effects of Granulocytic Myeloid-Derived Suppressor Cells on Tuberculosis Caused by Hypervirulent Mycobacteria. Journal of Infectious Diseases, v. 223, n. 3, p. 494-507, FEB 1 2021. (15/20432-8, 17/09110-4, 14/22986-8)

DE LIMA, DHEMERSON SOUZA; BOMFIM, CAIO C. B.; LEAL, VINICIUS N. C.; REIS, EDIONE C.; SOARES, JAINE L. S.; FERNANDES, FERNANDA P.; AMARAL, EDUARDO P.; LOURES, V, FLAVIO; OGUSKU, MAURICIO M.; D'IMPERIO LIMA, MARIA R.; et al. Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas. FRONTIERS IN IMMUNOLOGY, v. 11, OCT 21 2020. (15/20432-8, 15/23395-6, 15/50650-7)