title: Heme oxygenase-1 promotes the persistence of Leishmania chagasi infection.
abstract: Visceral leishmaniasis (VL) remains a major public health problem worldwide. This disease is highly associated with chronic inflammation and a lack of the cellular immune responses against Leishmania. It is important to identify major factors driving the successful establishment of the Leishmania infection to develop better tools for the disease control. Heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, and its role in VL has not been investigated. In this study, we evaluated the role of HO-1 in the infection by Leishmania infantum chagasi, the causative agent of VL cases in Brazil. We found that L. chagasi infection or lipophosphoglycan isolated from promastigotes triggered HO-1 production by murine macrophages. Interestingly, cobalt protoporphyrin IX, an HO-1 inductor, increased the parasite burden in both mouse and human-derived macrophages. Upon L. chagasi infection, macrophages from Hmox1 knockout mice presented significantly lower parasite loads when compared with those from wild-type mice. Furthermore, upregulation of HO-1 by cobalt protoporphyrin IX diminished the production of TNF-α and reactive oxygen species by infected murine macrophages and increased Cu/Zn superoxide dismutase expression in human monocytes. Finally, patients with VL presented higher systemic concentrations of HO-1 than healthy individuals, and this increase of HO-1 was reduced after antileishmanial treatment, suggesting that HO-1 is associated with disease susceptibility. Our data argue that HO-1 has a critical role in the L. chagasi infection and is strongly associated with the inflammatory imbalance during VL. Manipulation of HO-1 pathways during VL could serve as an adjunctive therapeutic approach.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/Fundação Oswaldo Cruz, Salvador 40295-001, Brazil.
authors.forename: Nívea F
authors.initials: NF
authors.lastname: Luz
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Feijó
authors.forename: Théo
authors.initials: T
authors.lastname: Araújo-Santos
authors.forename: Graziele Q
authors.initials: GQ
authors.lastname: Carvalho
authors.forename: Daniela
authors.initials: D
authors.lastname: Andrade
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Abánades
authors.forename: Enaldo V
authors.initials: EV
authors.lastname: Melo
authors.forename: Angela M
authors.initials: AM
authors.lastname: Silva
authors.forename: Cláudia I
authors.initials: CI
authors.lastname: Brodskyn
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
authors.forename: Aldina
authors.initials: A
authors.lastname: Barral
authors.forename: Rodrigo P
authors.initials: RP
authors.lastname: Soares
authors.forename: Roque P
authors.initials: RP
authors.lastname: Almeida
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Bozza
authors.forename: Valéria M
authors.initials: VM
authors.lastname: Borges
mesh_terms: D000818:Animals; D001938:Brazil; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006028:Glycosphingolipids / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007891:Leishmania / Q000276:immunology* / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D017319:Photosensitizing Agents / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D006028:Glycosphingolipids; D008565:Membrane Proteins; D017319:Photosensitizing Agents; D011524:Protoporphyrins; C008290:lipophosphonoglycan; C028025:protoporphyrin IX; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse