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dc.contributor.authorStüve, Philipp
dc.contributor.authorMinarrieta, Lucía
dc.contributor.authorErdmann, Hanna
dc.contributor.authorArnold-Schrauf, Catharina
dc.contributor.authorSwallow, Maxine
dc.contributor.authorGuderian, Melanie
dc.contributor.authorKrull, Freyja
dc.contributor.authorHölscher, Alexandra
dc.contributor.authorGhorbani, Peyman
dc.contributor.authorBehrends, Jochen
dc.contributor.authorAbraham, Wolf-Rainer
dc.contributor.authorHölscher, Christoph
dc.contributor.authorSparwasser, Tim D
dc.contributor.authorBerod, Luciana
dc.date.accessioned2018-11-28T10:14:16Z
dc.date.available2018-11-28T10:14:16Z
dc.date.issued2018-01-01
dc.identifier.issn1664-3224
dc.identifier.pmid29675017
dc.identifier.doi10.3389/fimmu.2018.00495
dc.identifier.urihttp://hdl.handle.net/10033/621589
dc.description.abstractMycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, is able to efficiently manipulate the host immune system establishing chronic infection, yet the underlying mechanisms of immune evasion are not fully understood. Evidence suggests that this pathogen interferes with host cell lipid metabolism to ensure its persistence. Fatty acid metabolism is regulated by acetyl-CoA carboxylase (ACC) 1 and 2; both isoforms catalyze the conversion of acetyl-CoA into malonyl-CoA, but have distinct roles. ACC1 is located in the cytosol, where it regulates de novo fatty acid synthesis (FAS), while ACC2 is associated with the outer mitochondrial membrane, regulating fatty acid oxidation (FAO). In macrophages, mycobacteria induce metabolic changes that lead to the cytosolic accumulation of lipids. This reprogramming impairs macrophage activation and contributes to chronic infection. In dendritic cells (DCs), FAS has been suggested to underlie optimal cytokine production and antigen presentation, but little is known about the metabolic changes occurring in DCs upon mycobacterial infection and how they affect the outcome of the immune response. We therefore determined the role of fatty acid metabolism in myeloid cells and T cells during Mycobacterium bovis BCG or Mtb infection, using novel genetic mouse models that allow cell-specific deletion of ACC1 and ACC2 in DCs, macrophages, or T cells. Our results demonstrate that de novo FAS is induced in DCs and macrophages upon M. bovis BCG infection. However, ACC1 expression in DCs and macrophages is not required to control mycobacteria. Similarly, absence of ACC2 did not influence the ability of DCs and macrophages to cope with infection. Furthermore, deletion of ACC1 in DCs or macrophages had no effect on systemic pro-inflammatory cytokine production or T cell priming, suggesting that FAS is dispensable for an intact innate response against mycobacteria. In contrast, mice with a deletion of ACC1 specifically in T cells fail to generate efficient T helper 1 responses and succumb early to Mtb infection. In summary, our results reveal ACC1-dependent FAS as a crucial mechanism in T cells, but not DCs or macrophages, to fight against mycobacterial infection.en_US
dc.publisherFrontiersen_US
dc.rightsAttribution-NonCommercial-ShareAlike 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/us/*
dc.subjectMycobacterium bovis BCGen_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectacetyl-CoA carboxylase 1en_US
dc.subjectacetyl-CoA carboxylase 2en_US
dc.subjectdendritic cellsen_US
dc.subjectfatty acid oxidationen_US
dc.subjectfatty acid synthesisen_US
dc.subjectmacrophagesen_US
dc.titleDe Novo Fatty Acid Synthesis During Mycobacterial Infection Is a Prerequisite for the Function of Highly Proliferative T Cells, But Not for Dendritic Cells or Macrophages.en_US
dc.typeArticleen_US
dc.contributor.departmentTWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
refterms.dateFOA2018-11-28T10:14:17Z
dc.source.journaltitleFrontiers in immunology


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