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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection
PLoS Pathogens, Volume 9, No. 10, Article e1003699, Year 2013
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Description
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. © 2013 Hurdayal et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3812013/bin/ppat.1003699.s001.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3812013/bin/ppat.1003699.s002.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3812013/bin/ppat.1003699.s003.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3812013/bin/ppat.1003699.s004.tif
Authors & Co-Authors
Hurdayal, Ramona
South Africa, Cape Town
University of Cape Town
Nieuwenhuizen, Natalie Eva
Germany, Berlin
Max Planck Institute for Infection Biology
Revaz-Breton, Mélanie
South Africa, Cape Town
University of Cape Town
Smith, Liezel
South Africa, Observatory
Groote Schuur Hospital
Hoving, Jennifer Claire
South Africa, Cape Town
University of Cape Town
Parihar, Suraj P.
South Africa, Cape Town
University of Cape Town
Reizis, Boris
United States, New York
Columbia University Irving Medical Center
Brombacher, Frank
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 54
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1371/journal.ppat.1003699
ISSN:
15537366
e-ISSN:
15537374
Research Areas
Genetics And Genomics