title: RIPK1 and PGAM5 Control Leishmania Replication through Distinct Mechanisms.
abstract: 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.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador-BA, 40110-060, Brazil;
authors.forename: Nivea
authors.initials: N
authors.lastname: Farias Luz
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Sakthi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Kendi
authors.identifier: 0000-0002-6471-9044
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Departamento de Medicina, Hospital Universitário, Universidade Federal de Sergipe, Aracaju 49010-390, Brazil;
authors.forename: Aline Silva
authors.initials: AS
authors.lastname: Barreto
authors.affiliation: Laboratorio de Imunopatologia, Centro de Pesquisa, Rene Rachou, Fundação Oswaldo Cruz, 30190-002 Belo Horizonte, Brazil;
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422;
authors.forename: Peter J
authors.identifier: 0000-0002-5110-9300
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Laboratorio de Imunopatologia, Centro de Pesquisa, Rene Rachou, Fundação Oswaldo Cruz, 30190-002 Belo Horizonte, Brazil;
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gazzinelli
authors.affiliation: Departamento de Medicina, Hospital Universitário, Universidade Federal de Sergipe, Aracaju 49010-390, Brazil;
authors.forename: Roque P
authors.initials: RP
authors.lastname: Almeida
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro-RJ, 21941-902, Brazil; and.
authors.forename: Marcelo T
authors.identifier: 0000-0003-3683-7550
authors.initials: MT
authors.lastname: Bozza
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador-BA, 40110-060, Brazil; francis.chan@umassmed.edu vborges@bahia.fiocruz.br.
authors.forename: Valeria M
authors.identifier: 0000-0002-2775-5409
authors.initials: VM
authors.lastname: Borges
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605; Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01605 francis.chan@umassmed.edu vborges@bahia.fiocruz.br.
authors.forename: Francis Ka-Ming
authors.identifier: 0000-0002-4803-8353
authors.initials: FK
authors.lastname: Chan
mesh_terms: D000818:Animals; D016923:Cell Death; D006418:Heme / Q000032:analysis / Q000494:pharmacology; D006790:Host-Parasite Interactions; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007891:Leishmania / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology*; D007896:Leishmaniasis / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000469:parasitology*; D007898:Leishmaniasis, Visceral / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000502:physiology; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D009569:Nitric Oxide; D006418:Heme; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases