Leishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemia

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dc.contributor.authorYilmaz I.C.
dc.contributor.authorDunuroglu E.
dc.contributor.authorAyanoglu I.C.
dc.contributor.authorIpekoglu E.M.
dc.contributor.authorYildirim M.
dc.contributor.authorGirginkardesler N.
dc.contributor.authorOzbel Y.
dc.contributor.authorToz S.
dc.contributor.authorOzbilgin A.
dc.contributor.authorAykut G.
dc.contributor.authorGursel I.
dc.contributor.authorGursel M.
dc.date.accessioned2024-07-22T08:03:47Z
dc.date.available2024-07-22T08:03:47Z
dc.date.issued2022
dc.description.abstractLeishmania parasites harbor a unique network of circular DNA known as kinetoplast DNA (kDNA). The role of kDNA in leishmania infections is poorly understood. Herein, we show that kDNA delivery to the cytosol of Leishmania major infected THP-1 macrophages provoked increased parasite loads when compared to untreated cells, hinting at the involvement of cytosolic DNA sensors in facilitating parasite evasion from the immune system. Parasite proliferation was significantly hindered in cGAS- STING- and TBK-1 knockout THP-1 macrophages when compared to wild type cells. Nanostring nCounter gene expression analysis on L. major infected wild type versus knockout cells revealed that some of the most upregulated genes including, Granulysin (GNLY), Chitotriosidase-1 (CHIT1), Sialomucin core protein 24 (CD164), SLAM Family Member 7 (SLAMF7), insulin-like growth factor receptor 2 (IGF2R) and apolipoprotein E (APOE) were identical in infected cGAS and TBK1 knockout cells, implying their involvement in parasite control. Amlexanox treatment (a TBK1 inhibitor) of L. major infected wild type cells inhibited both the percentage and the parasite load of infected THP-1 cells and delayed footpad swelling in parasite infected mice. Collectively, these results suggest that leishmania parasites might hijack the cGAS-STING-TBK1 signaling pathway to their own advantage and the TBK1 inhibitor amlexanox could be of interest as a candidate drug in treatment of cutaneous leishmaniasis. Copyright © 2022 Yilmaz, Dunuroglu, Ayanoglu, Ipekoglu, Yildirim, Girginkardesler, Ozbel, Toz, Ozbilgin, Aykut, Gursel and Gursel.
dc.identifier.DOI-ID10.3389/fimmu.2022.1007070
dc.identifier.issn16643224
dc.identifier.urihttp://akademikarsiv.cbu.edu.tr:4000/handle/123456789/12445
dc.language.isoEnglish
dc.publisherFrontiers Media S.A.
dc.rightsAll Open Access; Gold Open Access; Green Open Access
dc.subjectAnimals
dc.subjectChromogranin A
dc.subjectDNA
dc.subjectDNA, Kinetoplast
dc.subjectLeishmania
dc.subjectMacrophages
dc.subjectMembrane Proteins
dc.subjectMice
dc.subjectNucleotidyltransferases
dc.subjectParasitemia
dc.subjectParasites
dc.subjectProtein Serine-Threonine Kinases
dc.subjectSignal Transduction
dc.subjectamlexanox
dc.subjectkinetoplast DNA
dc.subjectprotein kinase
dc.subjectchromogranin A
dc.subjectDNA
dc.subjectkinetoplast DNA
dc.subjectmembrane protein
dc.subjectnucleotidyltransferase
dc.subjectTbk1 protein, mouse
dc.subjectArticle
dc.subjectatomic force microscopy
dc.subjectcontrolled study
dc.subjectDNA isolation
dc.subjectfluorescence microscopy
dc.subjectLeishmania
dc.subjectleishmaniasis
dc.subjectmacrophage
dc.subjectnonhuman
dc.subjectanimal
dc.subjectgenetics
dc.subjectmacrophage
dc.subjectmetabolism
dc.subjectmouse
dc.subjectparasite
dc.subjectparasitemia
dc.subjectsignal transduction
dc.titleLeishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemia
dc.typeArticle

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