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Registro Completo |
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Biblioteca(s): |
Embrapa Gado de Leite. |
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Data corrente: |
17/11/2025 |
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Data da última atualização: |
17/11/2025 |
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Tipo da produção científica: |
Artigo em Periódico Indexado |
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Autoria: |
GOMES, M. T.; MEDEIROS-DE-MORAES, I. M.; VIEIRA-DE-ABREU, A.; AZEVEDO-QUINTANILHA, I. G.; FONTES, T. M.; CARNEIRO, A. de B.; AZAMBUJA, P.; TOLLEY, N. D.; ROWLEY, J. W.; CARPINTER, B. A.; FERREIRA, M. U.; GONÇALVES-LOPES, R. M.; ROCHA, V. N.; NASCIMENTO, A. L. R.; CARVALHO, W. A.; SCOPEL, K. K. G.; CAMPBELL, R. A.; BOZZA, P. T.; WEYRICH, A. S.; ZIMMERMAN, G. A.; LACERDA, M. V. G.; FARIA NETO, H. C. C.; HOTTZ, E. M. |
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Afiliação: |
MILENA TAVARES GOMES, UNIVERSIDADE FEDERAL DE JUIZ DE FORA; ISABEL MATOS MEDEIROS-DE-MORAES, FUNDAÇÃO OSWALDO CRUZ; ADRIANA VIEIRA-DE-ABREU, UNIVERSITY OF UTAH; ISACLAUDIA G. AZEVEDO-QUINTANILHA, INSTITUTO OSWALDO CRUZ; THAYANE MODESTO FONTES, UNIVERSIDADE FEDERAL DE JUIZ DE FORA; ALAN DE BRITO CARNEIRO, UNIVERSITY OF ILLINOIS; PEDRO AZAMBUJA, FUNDAÇÃO OSWALDO CRUZ; NEAL D. TOLLEY, UNIVERSITY OF UTAH; JESSE W. ROWLEY, UNIVERSITY OF UTAH; BARBARA ALBUQUERQUE CARPINTER, UNIVERSIDADE FEDERAL DE JUIZ DE FORA; MARCELO U. FERREIRA, UNIVERSIDADE DE SÃO PAULO; RAQUEL M. GONÇALVES-LOPES, UNIVERSIDADE ESTADUAL DE CAMPINAS; VINICIUS N. ROCHA, UNIVERSIDADE FEDERAL DE JUIZ DE FORA; ANA LUCIA ROSA NASCIMENTO, UNIVERSIDADE ESTADUAL DO RIO DE JANEIRO; WANESSA ARAUJO CARVALHO, CNPGL; KÉZIA K. G. SCOPEL, UNIVERSIDADE FEDERAL DE JUIZ DE FORA; ROBERT A, CAMPBELL, WASHINGTON UNIVERSITY; PATRICIA TORRES BOZZA, INSTITUTO OSWALDO CRUZ; ANDREW S. WEYRICH, OKLAHOMA MEDICAL RESEARCH FOUNDATION; GUY A. ZIMMERMAN, UNIVERSITY OF UTAH; MARCUS V. G. LACERDA, FUNDAÇÃO DE MEDICINA TROPICAL DR. HEITOR VIEIRA DOURADO; HUGO C. CASTRO FARIA NETO, INSTITUTO OSWALDO CRUZ; EUGENIO DAMACENO HOTTZ, UNIVERSIDADE FEDERAL DE JUIZ DE FORA. |
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Título: |
Heme and hemozoin induce platelet cell death through UPR-induced apoptosis and ferroptosis in vivax malaria. |
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Ano de publicação: |
2025 |
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Fonte/Imprenta: |
Blood Advances, 2025. |
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DOI: |
https://doi.org/10.1182/bloodadvances.2024015623 |
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Idioma: |
Inglês |
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Notas: |
First online. |
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Conteúdo: |
Malaria is a highly prevalent infectious disease caused by Plasmodium parasites. Plasmodium intraerythrocytic replication leads to hemolysis-driven intermittent febrile crisis in patients. Additionally, the lysis of unparasitized red blood cells (RBC) contributes to anemia and endotoxemia. Because thrombocytopenia is an important feature of vivax and severe falciparum malaria, we hypothesized that increased hemolysis in malaria contributes to severe thrombocytopenia by releasing endogenous and parasite toxins (i.e., heme and hemozoin) capable of inducing programmed cell death in platelets. Using complementary biochemical, ultrastructural, pharmacological and molecular approaches, we examined response to stress and cell death pathways that were elevated in the transcriptome of platelets during vivax malaria and evaluated markers of hemolysis that correlated with thrombocytopenia. We found that heme in plasma from thrombocytopenic vivax malaria, but not nonthrombocytopenic vivax or falciparum malaria, induced platelet cell death ex vivo. Platelet stimulation with heme and hemozoin induced apoptotic and necrotic cell death features, with stronger necrosis triggered by hemozoin. Heme and hemozoin activated apoptotic caspases, but only heme induced calpain-dependent Bcl-xL degradation, which was not required for platelet apoptosis. We unmasked a caspase-independent intrinsic apoptosis program mechanism depending on the endoplasmic reticulum (ER)-stress sensor and unfolded protein response (UPR) trigger IRE-Iα. We observed inflammasome activation, but not pyroptosis. Instead, we distinguished a necrotic cell death feature consistent with ferroptosis dependent on lipid peroxidation and regulated by DGAT1/2 enzymes, which was the main pathway for hemozoin-induced thrombocytopenia in vitro. Taken together, our results identify novel pathways of regulated cell death in platelets that were associated with thrombocytopenia in malaria and may have potential implications for other hemolytic disorders. MenosMalaria is a highly prevalent infectious disease caused by Plasmodium parasites. Plasmodium intraerythrocytic replication leads to hemolysis-driven intermittent febrile crisis in patients. Additionally, the lysis of unparasitized red blood cells (RBC) contributes to anemia and endotoxemia. Because thrombocytopenia is an important feature of vivax and severe falciparum malaria, we hypothesized that increased hemolysis in malaria contributes to severe thrombocytopenia by releasing endogenous and parasite toxins (i.e., heme and hemozoin) capable of inducing programmed cell death in platelets. Using complementary biochemical, ultrastructural, pharmacological and molecular approaches, we examined response to stress and cell death pathways that were elevated in the transcriptome of platelets during vivax malaria and evaluated markers of hemolysis that correlated with thrombocytopenia. We found that heme in plasma from thrombocytopenic vivax malaria, but not nonthrombocytopenic vivax or falciparum malaria, induced platelet cell death ex vivo. Platelet stimulation with heme and hemozoin induced apoptotic and necrotic cell death features, with stronger necrosis triggered by hemozoin. Heme and hemozoin activated apoptotic caspases, but only heme induced calpain-dependent Bcl-xL degradation, which was not required for platelet apoptosis. We unmasked a caspase-independent intrinsic apoptosis program mechanism depending on the endoplasmic reticulum (ER)-stress sensor and unfolded protein... Mostrar Tudo |
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Palavras-Chave: |
Hemólise; Plaqueta; Trombocitopenia. |
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Thesagro: |
Malaria Aviaria. |
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Categoria do assunto: |
H Saúde e Patologia |
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Marc: |
LEADER 03349naa a2200457 a 4500
001 2181568
005 2025-11-17
008 2025 bl uuuu u00u1 u #d
024 7 $ahttps://doi.org/10.1182/bloodadvances.2024015623$2DOI
100 1 $aGOMES, M. T.
245 $aHeme and hemozoin induce platelet cell death through UPR-induced apoptosis and ferroptosis in vivax malaria.$h[electronic resource]
260 $c2025
500 $aFirst online.
520 $aMalaria is a highly prevalent infectious disease caused by Plasmodium parasites. Plasmodium intraerythrocytic replication leads to hemolysis-driven intermittent febrile crisis in patients. Additionally, the lysis of unparasitized red blood cells (RBC) contributes to anemia and endotoxemia. Because thrombocytopenia is an important feature of vivax and severe falciparum malaria, we hypothesized that increased hemolysis in malaria contributes to severe thrombocytopenia by releasing endogenous and parasite toxins (i.e., heme and hemozoin) capable of inducing programmed cell death in platelets. Using complementary biochemical, ultrastructural, pharmacological and molecular approaches, we examined response to stress and cell death pathways that were elevated in the transcriptome of platelets during vivax malaria and evaluated markers of hemolysis that correlated with thrombocytopenia. We found that heme in plasma from thrombocytopenic vivax malaria, but not nonthrombocytopenic vivax or falciparum malaria, induced platelet cell death ex vivo. Platelet stimulation with heme and hemozoin induced apoptotic and necrotic cell death features, with stronger necrosis triggered by hemozoin. Heme and hemozoin activated apoptotic caspases, but only heme induced calpain-dependent Bcl-xL degradation, which was not required for platelet apoptosis. We unmasked a caspase-independent intrinsic apoptosis program mechanism depending on the endoplasmic reticulum (ER)-stress sensor and unfolded protein response (UPR) trigger IRE-Iα. We observed inflammasome activation, but not pyroptosis. Instead, we distinguished a necrotic cell death feature consistent with ferroptosis dependent on lipid peroxidation and regulated by DGAT1/2 enzymes, which was the main pathway for hemozoin-induced thrombocytopenia in vitro. Taken together, our results identify novel pathways of regulated cell death in platelets that were associated with thrombocytopenia in malaria and may have potential implications for other hemolytic disorders.
650 $aMalaria Aviaria
653 $aHemólise
653 $aPlaqueta
653 $aTrombocitopenia
700 1 $aMEDEIROS-DE-MORAES, I. M.
700 1 $aVIEIRA-DE-ABREU, A.
700 1 $aAZEVEDO-QUINTANILHA, I. G.
700 1 $aFONTES, T. M.
700 1 $aCARNEIRO, A. de B.
700 1 $aAZAMBUJA, P.
700 1 $aTOLLEY, N. D.
700 1 $aROWLEY, J. W.
700 1 $aCARPINTER, B. A.
700 1 $aFERREIRA, M. U.
700 1 $aGONÇALVES-LOPES, R. M.
700 1 $aROCHA, V. N.
700 1 $aNASCIMENTO, A. L. R.
700 1 $aCARVALHO, W. A.
700 1 $aSCOPEL, K. K. G.
700 1 $aCAMPBELL, R. A.
700 1 $aBOZZA, P. T.
700 1 $aWEYRICH, A. S.
700 1 $aZIMMERMAN, G. A.
700 1 $aLACERDA, M. V. G.
700 1 $aFARIA NETO, H. C. C.
700 1 $aHOTTZ, E. M.
773 $tBlood Advances, 2025.
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Embrapa Gado de Leite (CNPGL) |
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