{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:46:13Z","timestamp":1789717573237,"version":"4.0.1"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multiple pathogen\u2010associated molecular patterns (PAMPs) on a pathogen's surface imply their simultaneous recognition by the host cell membrane\u2010located multiple PAMP\u2010specific Toll\u2010like receptors (TLRs). The TLRs on endosomes recognize internalized pathogen\u2010derived nucleic acids and trigger anti\u2010pathogen immune responses aimed at eliminating the intracellular pathogen. Whether the TLRs influence each other's expression and effector responses\u2014termed TLR interdependency\u2014remains unknown. Herein, we first probed the existence of TLR interdependencies and next determined how targeting TLR interdependencies might determine the outcome of <jats:italic>Leishmania<\/jats:italic> infection. We observed that TLRs selectively altered expression of their own and of other TLRs revealing novel TLR interdependencies. <jats:italic>Leishmania<\/jats:italic> <jats:italic>major<\/jats:italic>\u2014an intra\u2010macrophage parasite inflicting the disease cutaneous leishmaniasis in 88 countries\u2014altered this TLR interdependency unfolding a unique immune evasion mechanism. We targeted this TLR interdependency by selective silencing of rationally chosen TLRs and by stimulation with selective TLR ligands working out a novel phase\u2010specific treatment regimen. Targeting the TLR interdependency elicited a host\u2010protective anti\u2010leishmanial immune response and reduced parasite burden. To test whether this observation could be used as a scientific rationale for treating a potentially fatal <jats:italic>L<\/jats:italic>.\u00a0<jats:italic>donovani<\/jats:italic> infection, which causes visceral leishmaniasis, we targeted the inter\u2010TLR dependency adopting the same treatment regimen. We observed reduced splenic Leishman\u2013Donovan units accompanied by host\u2010protective immune response in susceptible BALB\/c mice. The TLR interdependency optimizes TLR\u2010induced immune response by a novel immunoregulatory framework and scientifically rationalizes targeting TLRs in tandem and in sequence for redirecting immune responses against an intracellular pathogen.<\/jats:p>","DOI":"10.1111\/imm.13364","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T07:23:00Z","timestamp":1620544980000},"page":"173-189","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Interdependencies between Toll\u2010like receptors in <i>Leishmania<\/i> infection"],"prefix":"10.1111","volume":"164","author":[{"given":"Divanshu","family":"Shukla","sequence":"first","affiliation":[{"name":"National Centre for Cell Science Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0957-9680","authenticated-orcid":false,"given":"Ashok","family":"Patidar","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uddipan","family":"Sarma","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Chauhan","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya Prakash","family":"Pandey","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science Pune India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshu Singh","family":"Chandel","sequence":"additional","affiliation":[{"name":"National Centre for Cell 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Minho Braga Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arup","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Trident Academy of Creative Technology Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5833-7912","authenticated-orcid":false,"given":"Bhaskar","family":"Saha","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science Pune India"},{"name":"Trident Academy of Creative Technology Bhubaneswar India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surajit","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Tripura University Agartala 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