title: Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi.
abstract: UNC93B1 associates with TLR3, 7, and 9, mediating their translocation from the endoplasmic reticulum to the endolysosome, thus allowing proper activation by microbial nucleic acids. We found that the triple-deficient 3d mice, which lack functional UNC93B1 as well as functional endosomal TLRs, are highly susceptible to infection with Trypanosoma cruzi. The enhanced parasitemia and mortality in 3d animals were associated with impaired proinflammatory response, including reduced levels of IL-12p40 and IFN-γ. Importantly, the phenotype of 3d mice was intermediary between MyD88(-/-) (highly susceptible) and TLR9(-/-) (moderately susceptible), indicating the involvement of an additional UN93B1-dependent TLR(s) on host resistance to T. cruzi. Hence, our experiments also revealed that TLR7 is a critical innate immune receptor involved in recognition of parasite RNA, induction of IL-12p40 by dendritic cells, and consequent IFN-γ by T lymphocytes. Furthermore, we show that upon T. cruzi infection, triple TLR3/7/9(-/-) mice had similar phenotype than 3d mice. These data imply that the nucleic acid-sensing TLRs are critical determinants of host resistance to primary infection with T. cruzi.
authors.affiliation: Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Braulia C
authors.initials: BC
authors.lastname: Caetano
authors.forename: Bianca B
authors.initials: BB
authors.lastname: Carmo
authors.forename: Mariane B
authors.initials: MB
authors.lastname: Melo
authors.forename: Anna
authors.initials: A
authors.lastname: Cerny
authors.forename: Sara L
authors.initials: SL
authors.lastname: dos Santos
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Bartholomeu
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D018512:Parasitemia / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D053762:Interleukin-12 Subunit p40; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C519703:TLR3 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D007371:Interferon-gamma