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RIPK1 AND PGAM5 CONTROL LEISHMANIA REPLICATION THROUGH DISTINCT MECHANISMS
Leishmaniose Cutânea
Morte celular
Proteína quinase
Heme
Medula óssea
Macrófagos
Leishmaniasis, Cutaneous
Cell death
Protein kinase
Heme
Bone marrow
Macrophages
Autor(es)
Afiliação
University of Massachusetts Medical School. Department of Pathology. Worcester, MA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
University of Massachusetts Medical School. Department of Pathology. Worcester, MA
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA
Universidade Federal de Sergipe. Hospital Universitário. Departamento de Medicina. Aracaju, SE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Laboratorio de Imunopatologia. Belo Horizonte, MG, Brasil
Pattern Recognition Receptor Discovery Performance Unit. Immuno-Inflammation Therapeutic Area, GlaxoSmithKline. Collegeville, PA
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA / Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Laboratorio de Imunopatologia. Belo Horizonte, MG, Brasil
Universidade Federal de Sergipe. Hospital Universitário. Departamento de Medicina. Aracaju, SE, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia. Departamento de Imunologia, Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
University of Massachusetts Medical School. Immunology and Microbiology Program. Worcester, MA / University of Massachusetts Medical School. Department of Pathology. Worcester, MA
University of Massachusetts Medical School. Department of Pathology. Worcester, MA
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA
Universidade Federal de Sergipe. Hospital Universitário. Departamento de Medicina. Aracaju, SE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Laboratorio de Imunopatologia. Belo Horizonte, MG, Brasil
Pattern Recognition Receptor Discovery Performance Unit. Immuno-Inflammation Therapeutic Area, GlaxoSmithKline. Collegeville, PA
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA / Fundação Oswaldo Cruz. Centro de Pesquisa Rene Rachou. Laboratorio de Imunopatologia. Belo Horizonte, MG, Brasil
Universidade Federal de Sergipe. Hospital Universitário. Departamento de Medicina. Aracaju, SE, Brasil
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia. Departamento de Imunologia, Rio de Janeiro, RJ, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
University of Massachusetts Medical School. Immunology and Microbiology Program. Worcester, MA / University of Massachusetts Medical School. Department of Pathology. Worcester, MA
Resumo em Inglês
Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow-derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1β expression in response to Leishmania However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1β secretion and NO production in bone marrow-derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host.
Palavras-chave
LeishmaniaLeishmaniose Cutânea
Morte celular
Proteína quinase
Heme
Medula óssea
Macrófagos
Palavras-chave em inglês
LeishmaniaLeishmaniasis, Cutaneous
Cell death
Protein kinase
Heme
Bone marrow
Macrophages
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