title: A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts.
abstract: Innate immune recognition of intracellular pathogens involves both extracellular and cytosolic surveillance mechanisms. The intracellular protozoan parasite Trypanosoma cruzi triggers a robust type I IFN response in both immune and nonimmune cell types. In this study, we report that signaling through TBK1 and IFN regulatory factor 3 is required for T. cruzi-mediated expression of IFN-beta. The TLR adaptors MyD88 and TRIF, as well as TLR4 and TLR3, were found to be dispensable, demonstrating that T. cruzi induces IFN-beta expression in a TLR-independent manner. The potential role for cytosolic dsRNA sensing pathways acting through RIG-I and MDA5 was ruled out because T. cruzi was shown to trigger robust expression of IFN-beta in macrophages lacking the MAVS/IPS1/VISA/CARDif adaptor protein. The failure of T. cruzi to activate HEK293-IFN-beta-luciferase cells, which are highly sensitive to cytosolic triggers of IFN-beta expression including Listeria, Sendai virus, and transfected dsRNA and dsDNA, further indicates that the parasite does not engage currently recognized cytosolic surveillance pathways. Together, these findings identify the existence of a novel TLR-independent pathogen-sensing mechanism in immune and nonimmune cells that converges on TBK1 and IFN regulatory factor 3 for activation of IFN-beta gene expression.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Anne-Danielle C
authors.initials: AD
authors.lastname: Chessler
authors.forename: Ludmila R P
authors.initials: LR
authors.lastname: Ferreira
authors.forename: Tun-Han
authors.initials: TH
authors.lastname: Chang
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Burleigh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008087:Listeria / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology; D029082:Sendai virus / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004247:DNA; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D017346:Protein Serine-Threonine Kinases; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; C512612:MAVS protein, mouse; C494232:IRF3 protein, human; C494233:Irf3 protein, mouse; C505371:MAVS protein, human; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C498588:Tbk1 protein, mouse; C403191:TBK1 protein, human