title: UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major.
abstract: The mammalian homolog B1 of Unc-93 Caenorhabditis elegans known as UNC93B1 is a chaperone protein that mediates translocation of the nucleic acid-sensing Toll-like receptors (TLRs) from the endoplasmic reticulum to the endolysosomes. The triple deficient (UNC93B1 mutant) mice have a functional single point mutation in the UNC93B1 that results in non-functional TLR3, TLR7, and TLR9. Herein, we demonstrate that UNC93B1 mutant mice, in the C57BL/6 (resistant) genetic background, are highly susceptible to Leishmania major infection. Enhanced swelling of the footpad was associated with high levels of interleukin 10, decreased levels of interferon γ, and increased parasitism. None of the single TLR3, TLR7, and TLR9 knock-out (KO) mice resemble the UNC93B1 mutant phenotype upon infection with L. major. Whereas the double TLR7/TLR9 KO showed a partial phenotype, the triple TLR3/TLR7/TLR9 KO mice were as susceptible as the UNC93B1 mutant mice, when infected with Leishmania parasites. Finally, we demonstrate that treatment with either anti-interleukin 10 receptor monoclonal antibody or recombinant interleukin 12 restored a robust anti-parasite TH1 response and reverted the susceptible phenotype of UNC93B1 mutant mice. Altogether, our results indicate the redundant and essential role of nucleic acid-sensing TLR3, TLR7 and TLR9 in inducing interleukin 12, development of a TH1 response, and resistance to L. major infection in resistant C57BL/6 mice.
authors: University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Bruno Luiz Fonseca
authors: BL
authors: Schamber-Reis
authors: Patricia M
authors: PM
authors: Petritus
authors: Braulia C
authors: BC
authors: Caetano
authors: Espiridion R
authors: ER
authors: Martinez
authors: Kendi
authors: K
authors: Okuda
authors: Douglas
authors: D
authors: Golenbock
authors: Phillip
authors: P
authors: Scott
authors: Ricardo T
authors: RT
authors: Gazzinelli
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005260:Female; D006790:Host-Parasite Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology* / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009696:Nucleic Acids / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D026901:Membrane Transport Proteins; D009696:Nucleic Acids; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma