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dc.contributor.authorMesquita, Inês
dc.contributor.authorFerreira, Carolina
dc.contributor.authorMoreira, Diana
dc.contributor.authorKluck, George Eduardo Gabriel
dc.contributor.authorBarbosa, Ana Margarida
dc.contributor.authorTorrado, Egídio
dc.contributor.authorDinis-Oliveira, Ricardo Jorge
dc.contributor.authorGonçalves, Luís Gafeira
dc.contributor.authorBeauparlant, Charles-Joly
dc.contributor.authorDroit, Arnaud
dc.contributor.authorBerod, Luciana
dc.contributor.authorSparwasser, Tim
dc.contributor.authorBodhale, Neelam
dc.contributor.authorSaha, Bhaskar
dc.contributor.authorRodrigues, Fernando
dc.contributor.authorCunha, Cristina
dc.contributor.authorCarvalho, Agostinho
dc.contributor.authorCastro, António Gil
dc.contributor.authorEstaquier, Jérôme
dc.contributor.authorSilvestre, Ricardo
dc.date.accessioned2022-06-13T12:31:38Z
dc.date.available2022-06-13T12:31:38Z
dc.date.issued2020-03-24
dc.date.submitted2019-09-02
dc.identifier.pmid32209468
dc.identifier.doi10.1016/j.celrep.2020.02.098
dc.identifier.urihttp://hdl.handle.net/10033/623219
dc.description.abstractHypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.en_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectFASNen_US
dc.subjectHIF-1αen_US
dc.subjectSREBP-1cen_US
dc.subjectacetateen_US
dc.subjectlipogenesisen_US
dc.subjectmacrophagesen_US
dc.subjectmyeloid cellsen_US
dc.subjectvisceral leishmaniasisen_US
dc.titleThe Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis.en_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.eissn2211-1247
dc.identifier.journalCell reportsen_US
dc.source.volume30
dc.source.issue12
dc.source.beginpage4052
dc.source.endpage4064.e7
refterms.dateFOA2022-06-13T12:31:39Z
dc.source.journaltitleCell reports
dc.source.countryUnited States
dc.source.countryUnited States


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International