Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection

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dc.contributor.authorHurdayal, Ramonaen_ZA
dc.contributor.authorNieuwenhuizen, Natalie Een_ZA
dc.contributor.authorRevaz-Breton, Mélanieen_ZA
dc.contributor.authorSmith, Liezelen_ZA
dc.contributor.authorHoving, Jennifer Cen_ZA
dc.contributor.authorParihar, Suraj Pen_ZA
dc.contributor.authorReizis, Borisen_ZA
dc.contributor.authorBrombacher, Franken_ZA
dc.date.accessioned2016-01-11T06:53:32Z
dc.date.available2016-01-11T06:53:32Z
dc.date.issued2013en_ZA
dc.description.abstractIn BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions.en_ZA
dc.identifier.apacitationHurdayal, R., Nieuwenhuizen, N. E., Revaz-Breton, M., Smith, L., Hoving, J. C., Parihar, S. P., ... Brombacher, F. (2013). Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. <i>PLoS One</i>, http://hdl.handle.net/11427/16283en_ZA
dc.identifier.chicagocitationHurdayal, Ramona, Natalie E Nieuwenhuizen, Mélanie Revaz-Breton, Liezel Smith, Jennifer C Hoving, Suraj P Parihar, Boris Reizis, and Frank Brombacher "Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16283en_ZA
dc.identifier.citationHurdayal, R., Nieuwenhuizen, N. E., Revaz-Breton, M., Smith, L., Hoving, J. C., Parihar, S. P., ... & Brombacher, F. (2013). Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. PLoS pathogens, 9(10), e1003699. doi:10.1371/journal.ppat.1003699en_ZA
dc.identifier.ris TY - Journal Article AU - Hurdayal, Ramona AU - Nieuwenhuizen, Natalie E AU - Revaz-Breton, Mélanie AU - Smith, Liezel AU - Hoving, Jennifer C AU - Parihar, Suraj P AU - Reizis, Boris AU - Brombacher, Frank AB - In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions. DA - 2013 DB - OpenUCT DO - 10.1371/journal.ppat.1003699 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection TI - Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection UR - http://hdl.handle.net/11427/16283 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16283
dc.identifier.urihttp://dx.doi.org/10.1371/journal.ppat.1003699
dc.identifier.vancouvercitationHurdayal R, Nieuwenhuizen NE, Revaz-Breton M, Smith L, Hoving JC, Parihar SP, et al. Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection. PLoS One. 2013; http://hdl.handle.net/11427/16283.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2013 Hurdayal et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plospathogensen_ZA
dc.subject.otherLeishmania majoren_ZA
dc.subject.otherParasitic diseasesen_ZA
dc.subject.otherMacrophagesen_ZA
dc.subject.otherLymph nodesen_ZA
dc.subject.otherSpleenen_ZA
dc.subject.otherDendritic cellsen_ZA
dc.subject.otherParasite replicationen_ZA
dc.subject.otherCytokinesen_ZA
dc.titleDeletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infectionen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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