title: Autophagy Is an Innate Mechanism Associated with Leprosy Polarization.
abstract: Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Bruno Jorge de Andrade
authors.initials: BJ
authors.lastname: Silva
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Mayara Garcia de Mattos
authors.initials: MG
authors.lastname: Barbosa
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Priscila Ribeiro
authors.initials: PR
authors.lastname: Andrade
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Helen
authors.initials: H
authors.lastname: Ferreira
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: José Augusto da Costa
authors.initials: JA
authors.lastname: Nery
authors.affiliation: Structural Biology Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Suzana
authors.initials: S
authors.lastname: Côrte-Real
authors.affiliation: Evandro Chagas National Institute of Infectology; FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Gilberto Marcelo Sperandio
authors.initials: GM
authors.lastname: da Silva
authors.affiliation: Laboratory Animal House; Lauro de Souza Lima Institute; São Paulo, Brazil.
authors.forename: Patricia Sammarco
authors.initials: PS
authors.lastname: Rosa
authors.affiliation: Department of Dermatology; University of Cologne; Cologne, Germany.|Center for Molecular Medicine; University of Cologne; Cologne, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Fabri
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Leprosy Laboratory; Oswaldo Cruz Institute; Oswaldo Cruz Foundation, FIOCRUZ; Rio de Janeiro, Brazil.
authors.forename: Roberta Olmo
authors.identifier: 0000-0001-8471-4227
authors.initials: RO
authors.lastname: Pinheiro
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000276:immunology; D007918:Leprosy / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology; D016133:Polymerase Chain Reaction; D012867:Skin / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D059467:Transcriptome; D055815:Young Adult
chemical_list: D007371:Interferon-gamma