UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major
Authors
Schamber-Reis, Bruno Luiz FonsecaPetritus, Patricia M.
Caetano, Braulia C.
Martinez, Espiridion R.
Okuda, Kendi
Golenbock, Douglas T.
Scott, Phillip
Gazzinelli, Ricardo T.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2013-03-08Keywords
AnimalsAntigens, CD4
Cells, Cultured
Disease Resistance
Female
Host-Parasite Interactions
Interferon-gamma
Interleukin-10
Leishmania major
Leishmaniasis, Cutaneous
Membrane Transport Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Nucleic Acids
Th1 Cells
Time Factors
Toll-Like Receptor 3
Toll-Like Receptor 7
Toll-Like Receptor 9
Toll-Like Receptors
Cytokines
Interferon
Innate Immunity
Leishmania
MyD88
Toll-like Receptors (TLR)
UNC93B1
Immunology of Infectious Disease
Metadata
Show full item recordAbstract
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 gamma, 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.Source
J Biol Chem. 2013 Mar 8;288(10):7127-36. doi: 10.1074/jbc.M112.407684. Link to article on publisher's siteDOI
10.1074/jbc.M112.407684Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29210PubMed ID
23325805Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M112.407684
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