{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:19:50Z","timestamp":1790702390938,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>IL-1R\/TLR signaling plays a significant role in sensing harmful foreign pathogens and mounting effective innate and adaptive immune responses. However, the precise mechanism by which Leishmania donovani, an obligate intramacrophagic pathogen, breaches IL-1R\/TLR signaling and host-protective immunity remains obscure. In this study, we report the novel biphasic role of Toll-interacting protein (Tollip), a negative regulator of the IL-1R\/TLR pathway, in the disease progression of experimental visceral leishmaniasis. We observed that during early hours of infection, L. donovani induced phosphorylation of IRAK-1, resulting in the release of Tollip from the IL-1R\u2013associated kinase (IRAK)-1 complex in J774 macrophages, which then acted as an endocytic adaptor on cell surface IL-1R1 and promoted its lysosomal degradation. In the later stage, Tollip shuttled back to IRAK-1, thereby inhibiting IRAK-1 phosphorylation in association with IRAK-M to neutralize downstream TLR signaling in infected macrophages. Moreover, during late infection, L. donovani enhanced nuclear translocation and recruitment of transcription factors early growth response protein 2, NF erythroid 2\u2013related factor 2, and Ahr on Tollip promoter for its induction. Small interfering RNA\u2013mediated silencing of Tollip in infected macrophages significantly enhanced NF-\u03baB activation and induced host-defensive IL-12 and TNF-\u03b1 synthesis, thereby reducing amastigote multiplication. Likewise, abrogation of Tollip in L. donovani\u2013infected BALB\/c mice resulted in STAT-1\u2013, IRF-1\u2013, and NF-\u03baB\u2013mediated upregulation of host-protective cytokines and reduced organ parasite burden, thereby implicating its role in disease aggravation. Taken together, we conclude that L. donovani exploited the multitasking function of Tollip for its own establishment through downregulating IL-1R1\/TLR signaling in macrophages.<\/jats:p>","DOI":"10.4049\/jimmunol.1800062","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T15:16:40Z","timestamp":1529075800000},"page":"957-970","source":"Crossref","is-referenced-by-count":35,"title":["<i>Leishmania donovani<\/i> Exploits Tollip, a Multitasking Protein, To Impair TLR\/IL-1R Signaling for Its Survival in the Host"],"prefix":"10.1093","volume":"201","author":[{"given":"Naveen","family":"Parmar","sequence":"first","affiliation":[{"name":"Division of Parasitology, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]},{"name":"Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110001 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragya","family":"Chandrakar","sequence":"additional","affiliation":[{"name":"Division of Parasitology, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]},{"name":"Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110001 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preeti","family":"Vishwakarma","sequence":"additional","affiliation":[{"name":"Division of Parasitology, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]},{"name":"Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110001 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Singh","sequence":"additional","affiliation":[{"name":"Electron Microscopy Unit, Sophisticated Analytical Instrument Facility, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan","family":"Mitra","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110001 ,","place":["India"]},{"name":"Electron Microscopy Unit, Sophisticated Analytical Instrument Facility, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanta","family":"Kar","sequence":"additional","affiliation":[{"name":"Division of Parasitology, Council of Scientific and Industrial Research\u2013Central Drug Research Institute , Lucknow 226031 ,","place":["India"]},{"name":"Academy of Scientific and Innovative Research , Anusandhan Bhawan, New Delhi 110001 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"2025030417571059100_r1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. 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