title: Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice.
abstract: "Triple-defective" (3d) mice carrying a mutation in UNC93B1, a chaperone for the endosomal nucleic acid-sensing (NAS) Toll-like receptors TLR3, TLR7, and TLR9, are highly susceptible to Toxoplasma gondii infection. However, none of the single or even the triple NAS-TLR-deficient animals recapitulated the 3d susceptible phenotype to experimental toxoplasmosis. Investigating this further, we found that while parasite RNA and DNA activate innate immune responses via TLR7 and TLR9, TLR11 and TLR12 working as heterodimers are required for sensing and responding to Toxoplasma profilin. Consequently, the triple TLR7/TLR9/TLR11-deficient mice are highly susceptible to T. gondii infection, recapitulating the phenotype of 3d mice. Humans lack functional TLR11 and TLR12 genes. Consistently, human cells produce high levels of proinflammatory cytokines in response to parasite-derived RNA and DNA, but not to Toxoplasma profilin, supporting a more critical role for NAS-TLRs in human toxoplasmosis.
authors.affiliation: University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Warrison A
authors.initials: WA
authors.lastname: Andrade
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Souza
authors.forename: Espiridion
authors.initials: E
authors.lastname: Ramos-Martinez
authors.forename: Kamalpreet
authors.initials: K
authors.lastname: Nagpal
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Dutra
authors.forename: Mariane B
authors.initials: MB
authors.lastname: Melo
authors.forename: Daniella C
authors.initials: DC
authors.lastname: Bartholomeu
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D000818:Animals; D016054:DNA, Protozoan / Q000235:genetics / Q000276:immunology; D019281:Dimerization; D060467:Disease Resistance; D005260:Female; D006790:Host-Parasite Interactions; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016053:RNA, Protozoan / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology
chemical_list: D016054:DNA, Protozoan; D008562:Membrane Glycoproteins; D016053:RNA, Protozoan; C482903:Tlr11 protein, mouse; C539092:Tlr12 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors