title: IL-27 enhances Leishmania amazonensis infection via ds-RNA dependent kinase (PKR) and IL-10 signaling.
abstract: The protozoan parasite Leishmania infects and replicates in macrophages, causing a spectrum of diseases in the human host, varying from cutaneous to visceral clinical forms. It is known that cytokines modulate the immunological response against Leishmania and are relevant for infection resolution. Here, we report that Interleukin (IL)-27 increases Leishmania amazonensis replication in human and murine macrophages and that the blockage of the IL-10 receptor on the surface of infected cells abolished the IL-27-mediated enhancement of Leishmania growth. IL-27 induced the activation/phosphorylation of protein kinase R (PKR) in macrophages, and PKR blockage or PKR gene deletion abrogated the enhancement of the parasite growth driven by IL-27, as well as the L. amazonensis-induced macrophage production of IL-27. We also observed that L. amazonensis-induced expression of IL-27 depends on type I interferon signaling and the engagement of Toll-like receptor 2. Treatment of Leishmania-infected mice with IL-27 increased lesion size and parasite loads in the footpad and lymph nodes of infected animals, indicating that this cytokine exerts a local and a systemic effect on parasite growth and propagation. In conclusion, we show that IL-27 is a L. amazonensis-enhancing factor and that the PKR/IFN1 axis and IL-10 are critical mediators of this IL-27 induced effect.
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Barreto-de-Souza
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Pedro L C
authors.initials: PL
authors.lastname: Ferreira
authors.affiliation: Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Aislan de Carvalho
authors.initials: Ade C
authors.lastname: Vivarini
authors.affiliation: Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Teresa
authors.initials: T
authors.lastname: Calegari-Silva
authors.affiliation: Laboratory of Immunobiology of Leishmaniasis, Paulo de Goes Institute of Microbiology, Department of Immunology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Deivid Costa
authors.initials: DC
authors.lastname: Soares
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Regis
authors.affiliation: Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Renata M S
authors.initials: RM
authors.lastname: Pereira
authors.affiliation: Laboratory of Inflammatory Genes, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Aristóbolo M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Laboratory of Immunobiology of Leishmaniasis, Paulo de Goes Institute of Microbiology, Department of Immunology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Elvira M
authors.initials: EM
authors.lastname: Saraiva
authors.affiliation: Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; National Institute of Science and Technology, Translational Research in Health and Environment in the Amazon Region (INCT-IMPeTAM), Brazil. Electronic address: lopesu@biof.ufrj.br.
authors.forename: Ulisses G
authors.initials: UG
authors.lastname: Lopes
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil. Electronic address: dumith@ioc.fiocruz.br.
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D064094:Interleukin-27 / Q000378:metabolism* / Q000494:pharmacology; D007894:Leishmania mexicana; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D064094:Interleukin-27; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D019892:eIF-2 Kinase
keywords: IL-10; IL-27; Leishmania; Macrophages; PKR