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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buir.contributor.authorYıldırım, Muzaffer
buir.contributor.authorAykut, Gamze
buir.contributor.authorGursel, Ihsan
buir.contributor.orcidAykut, Gamze|0000-0003-2184-8628
buir.contributor.orcidGursel, Ihsan|0000-0003-3761-1166
dc.citation.epage12en_US
dc.citation.spage1en_US
dc.citation.volumeNumber13en_US
dc.contributor.authorYilmaz, Ismail Cem
dc.contributor.authorDunuroglu, Emre
dc.contributor.authorAyanoglu, Ihsan Cihan
dc.contributor.authorIpekoglu, Emre Mert
dc.contributor.authorYıldırım, Muzaffer
dc.contributor.authorGirginkardesler, Nogay
dc.contributor.authorOzbel, Yusuf
dc.contributor.authorToz, Seray
dc.contributor.authorOzbilgin, Ahmet
dc.contributor.authorAykut, Gamze
dc.contributor.authorGursel, Ihsan
dc.date.accessioned2023-03-02T08:18:44Z
dc.date.available2023-03-02T08:18:44Z
dc.date.issued2022-11-02
dc.departmentDepartment of Molecular Biology and Geneticsen_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. Copyright © 2022 Yilmaz, Dunuroglu, Ayanoglu, Ipekoglu, Yildirim, Girginkardesler, Ozbel, Toz, Ozbilgin, Aykut, Gursel and Gursel.en_US
dc.description.provenanceSubmitted by Cem Çağatay Akgün (cem.akgun@bilkent.edu.tr) on 2023-03-02T08:18:44Z No. of bitstreams: 1 Leishmania_kinetoplast_DNA_contributes_to_parasite_burden_in_infected_macrophages_Critical_role_of_the_cGAS-STING-TBK1_signaling_pathway_in_macrophage_parasitemia.pdf: 5331229 bytes, checksum: 1e8e166828bbafddcc6c3bee1fbcee38 (MD5)en
dc.description.provenanceMade available in DSpace on 2023-03-02T08:18:44Z (GMT). No. of bitstreams: 1 Leishmania_kinetoplast_DNA_contributes_to_parasite_burden_in_infected_macrophages_Critical_role_of_the_cGAS-STING-TBK1_signaling_pathway_in_macrophage_parasitemia.pdf: 5331229 bytes, checksum: 1e8e166828bbafddcc6c3bee1fbcee38 (MD5) Previous issue date: 2022-11-02en
dc.identifier.doi10.3389/fimmu.2022.1007070en_US
dc.identifier.issn16643224
dc.identifier.urihttp://hdl.handle.net/11693/112011
dc.language.isoEnglishen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.isversionofhttps://dx.doi.org/10.3389/fimmu.2022.1007070en_US
dc.source.titleFrontiers in Immunologyen_US
dc.subject2'3'-cGAMPen_US
dc.subjectAmlexanoxen_US
dc.subjectCgasen_US
dc.subjectH151en_US
dc.subjectKinetoplast DNA (Kdna)en_US
dc.subjectLeishmaniaen_US
dc.subjectSTINGen_US
dc.subjectTBK1en_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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