Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection

dc.contributor.authorLeal-Calvo, Thyago
dc.contributor.authorMartins, Bruna Leticia [UNESP]
dc.contributor.authorBertoluci, Daniele Ferreira [UNESP]
dc.contributor.authorRosa, Patricia Sammarco [UNESP]
dc.contributor.authorCamargo, Rodrigo Mendes de [UNESP]
dc.contributor.authorGermano, Giovanna Vale [UNESP]
dc.contributor.authorBrito de Souza, Vania Nieto [UNESP]
dc.contributor.authorPereira Latini, Ana Carla [UNESP]
dc.contributor.authorMoraes, Milton Ozorio
dc.contributor.institutionFiocruz MS
dc.contributor.institutionInst Lauro de Souza Lima
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.description.abstractLeprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.en
dc.description.affiliationFiocruz MS, Lab Hanseniase, Inst Oswaldo Cruz, Rio De Janeiro, Brazil
dc.description.affiliationInst Lauro de Souza Lima, Div Pesquisa & Ensino, Bauru, SP, Brazil
dc.description.affiliationUniv Estadual Paulista, Fac Med Botucatu, Dept Doencas Trop, Botucatu, SP, Brazil
dc.description.affiliationUnespUniv Estadual Paulista, Fac Med Botucatu, Dept Doencas Trop, Botucatu, SP, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIdFAPERJ: E_09/2019
dc.description.sponsorshipIdFAPERJ: E_34/2014 -PENSA RIO
dc.description.sponsorshipIdCNPq: 313657/2018-1
dc.description.sponsorshipIdCNPq: 4000170/20172
dc.description.sponsorshipIdFAPESP: 2015/01744-9
dc.identifier.citationFrontiers In Immunology. Lausanne: Frontiers Media Sa, v. 12, 12 p., 2021.
dc.publisherFrontiers Media Sa
dc.relation.ispartofFrontiers In Immunology
dc.sourceWeb of Science
dc.subjectMycobacterium leprae
dc.subjecthost-directed therapy
dc.titleLarge-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infectionen
dcterms.rightsHolderFrontiers Media Sa