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    UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major

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    Authors
    Schamber-Reis, Bruno Luiz Fonseca
    Petritus, 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 Immunology
    Document Type
    Journal Article
    Publication Date
    2013-03-08
    Keywords
    Animals
    Antigens, 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
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    Link to Full Text
    http://dx.doi.org/10.1074/jbc.M112.407684
    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 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 site
    DOI
    10.1074/jbc.M112.407684
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29210
    PubMed ID
    23325805
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M112.407684
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