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.authoridIpekoglu, Emre Mert/0000-0003-3104-7509
dc.authoridAyanoglu, Ihsan Cihan/0000-0003-4300-1401
dc.authorscopusid57216710105
dc.authorscopusid57970157300
dc.authorscopusid57200036217
dc.authorscopusid57192423745
dc.authorscopusid57193664664
dc.authorscopusid6507143975
dc.authorscopusid6603630554
dc.authorwosidYildirim, Muzaffer/HJH-5312-2023
dc.authorwosidAyanoğlu, İhsan Cihan/AAZ-5565-2020
dc.contributor.authorYilmaz, Ismail Cem
dc.contributor.authorDunuroglu, Emre
dc.contributor.authorAyanoglu, Ihsan Cihan
dc.contributor.authorIpekoglu, Emre Mert
dc.contributor.authorYildirim, Muzaffer
dc.contributor.authorGirginkardesler, Nogay
dc.contributor.authorOzbel, Yusuf
dc.date.accessioned2023-01-12T20:15:23Z
dc.date.available2023-01-12T20:15:23Z
dc.date.issued2022
dc.departmentN/A/Departmenten_US
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.en_US
dc.description.sponsorshipTUBITAK; [115S073]; [219S678]en_US
dc.description.sponsorshipFunding This work is supported by TUBITAK grants 115S073 and 219S678 to MG.en_US
dc.identifier.doi10.3389/fimmu.2022.1007070
dc.identifier.issn1664-3224
dc.identifier.pmid36405710en_US
dc.identifier.scopus2-s2.0-85142149871en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3389/fimmu.2022.1007070
dc.identifier.urihttps://hdl.handle.net/11454/78457
dc.identifier.volume13en_US
dc.identifier.wosWOS:000885619300001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherFrontiers Media Saen_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectleishmaniaen_US
dc.subjectkinetoplast DNA (kDNA)en_US
dc.subjectcGASen_US
dc.subjectSTINGen_US
dc.subjectTBK1en_US
dc.subjectamlexanoxen_US
dc.subject2'3'-cGAMPen_US
dc.subjectH151en_US
dc.subjectEvolutionen_US
dc.subjectEpidemiologyen_US
dc.subjectMexicanaen_US
dc.subjectTlr9en_US
dc.subjectAmpen_US
dc.titleLeishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemiaen_US
dc.typeArticleen_US

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