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Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni

Keratinocytes represent the major cell type in the skin. During cutaneous leishmaniasis (CL) and schistosomiasis, the skin is important during the parasite life cycle. While Th1 immunity is required to control CL, protection during schistosomiasis requires Th2 immunity. Paradoxically, Th2 characteri...

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Main Author: Govender, Melissa
Other Authors: Brombacher, Frank
Format: Thesis
Language:English
Published: Division of Immunology 2017
Subjects:
Clinical Sciences and Immunology
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access_status_str Open Access
author Govender, Melissa
author2 Brombacher, Frank
author_browse Brombacher, Frank
Govender, Melissa
author_facet Brombacher, Frank
Govender, Melissa
author_sort Govender, Melissa
collection Thesis
description Keratinocytes represent the major cell type in the skin. During cutaneous leishmaniasis (CL) and schistosomiasis, the skin is important during the parasite life cycle. While Th1 immunity is required to control CL, protection during schistosomiasis requires Th2 immunity. Paradoxically, Th2 characteristic IL-4 secreted early during L. major infection in mice, can drive a Th1 response by instructing dendritic cells to produce IL-12. Additionally, keratinocytes at the site of L. major infection in C57BL/6 mice, were postulated to be the source of the IL-4. We investigated if IL-4/IL-13 signalling via the IL-4Rα on keratinocytes contributed to early immunity during CL and schistosomiasis. Keratinocyte-specific IL-4Rα deficient (KRT14creIL-4Rα-/lox) BALB/c and C57BL/6 mice were generated by gene targeting and site-specific recombination (cre/loxP) under control of the KRT14 locus. In the L. major footpad model, KRT14creIL-4Rα-/lox BALB/c mice developed increased swelling, high parasite burdens, and cytokine and antibody secretion similar to littermate controls. L. major-infected KRT14creIL-4Rα-/lox C57BL/6 mice had decreased footpad swelling, low parasite burdens, a dominant Th1 cytokine response, and low type 1 and 2 antibody titres, similar to littermate control and resistant C57BL/6. In the L major ear model, KRT14creIL-4Rα-/lox BALB/c mice developed increased swelling, high parasite burdens, Th1 and Th2 cytokines, and high antibody titres, similar to littermate controls. L. major LV39-infected KRT14creIL-4Rα-/lox BALB/c mice showed significantly decreased parasite burdens in the ear, compared to littermate controls. L. major-infected KRT14creIL-4Rα-/lox C57BL/6 mice in the ear model, had decreased swelling, low parasite burdens, a dominant Th1 immune response, and low type 1 and 2 antibody titres, similar to littermate control and C57BL/6 mice. In the Schistosoma model, survival of S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice was similar to littermate controls during mortality studies. During acute infection, S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice showed gut pathology, hepatosplenomegaly, cytokine production, low type 1 and high type 2 antibodies, similar to littermate controls. In comparison to littermate controls, S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice had smaller granulomas. Collectively, our results indicate that IL-4/IL-13 signalling through the IL-4Rα on keratinocytes is not required for control during CL or acute schistosomiasis, but does contribute to efficient granuloma formation during acute schistosomiasis.
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institution University of Cape Town (South Africa)
language eng
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license_str Not specified — see source repository
provenance_str_mv Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository
publishDate 2017
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spelling oai:open.uct.ac.za:11427/24890 Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni Govender, Melissa Brombacher, Frank Hurdayal, Ramona Guler, Reto Clinical Sciences and Immunology Keratinocytes represent the major cell type in the skin. During cutaneous leishmaniasis (CL) and schistosomiasis, the skin is important during the parasite life cycle. While Th1 immunity is required to control CL, protection during schistosomiasis requires Th2 immunity. Paradoxically, Th2 characteristic IL-4 secreted early during L. major infection in mice, can drive a Th1 response by instructing dendritic cells to produce IL-12. Additionally, keratinocytes at the site of L. major infection in C57BL/6 mice, were postulated to be the source of the IL-4. We investigated if IL-4/IL-13 signalling via the IL-4Rα on keratinocytes contributed to early immunity during CL and schistosomiasis. Keratinocyte-specific IL-4Rα deficient (KRT14creIL-4Rα-/lox) BALB/c and C57BL/6 mice were generated by gene targeting and site-specific recombination (cre/loxP) under control of the KRT14 locus. In the L. major footpad model, KRT14creIL-4Rα-/lox BALB/c mice developed increased swelling, high parasite burdens, and cytokine and antibody secretion similar to littermate controls. L. major-infected KRT14creIL-4Rα-/lox C57BL/6 mice had decreased footpad swelling, low parasite burdens, a dominant Th1 cytokine response, and low type 1 and 2 antibody titres, similar to littermate control and resistant C57BL/6. In the L major ear model, KRT14creIL-4Rα-/lox BALB/c mice developed increased swelling, high parasite burdens, Th1 and Th2 cytokines, and high antibody titres, similar to littermate controls. L. major LV39-infected KRT14creIL-4Rα-/lox BALB/c mice showed significantly decreased parasite burdens in the ear, compared to littermate controls. L. major-infected KRT14creIL-4Rα-/lox C57BL/6 mice in the ear model, had decreased swelling, low parasite burdens, a dominant Th1 immune response, and low type 1 and 2 antibody titres, similar to littermate control and C57BL/6 mice. In the Schistosoma model, survival of S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice was similar to littermate controls during mortality studies. During acute infection, S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice showed gut pathology, hepatosplenomegaly, cytokine production, low type 1 and high type 2 antibodies, similar to littermate controls. In comparison to littermate controls, S. mansoni-infected KRT14creIL-4Rα-/lox BALB/c mice had smaller granulomas. Collectively, our results indicate that IL-4/IL-13 signalling through the IL-4Rα on keratinocytes is not required for control during CL or acute schistosomiasis, but does contribute to efficient granuloma formation during acute schistosomiasis. 2017-08-17T14:15:06Z 2017-08-17T14:15:06Z 2017 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/24890 eng application/pdf Division of Immunology Faculty of Health Sciences University of Cape Town
spellingShingle Clinical Sciences and Immunology
Govender, Melissa
Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
thesis_degree_str Doctoral
title Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
title_full Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
title_fullStr Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
title_full_unstemmed Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
title_short Investigating the role of IL-4/IL-13 signalling through the IL-4 receptor alpha (IL-4Rα) on keratinocytes in murine models of Leishmania major and Schistosoma mansoni
title_sort investigating the role of il 4 il 13 signalling through the il 4 receptor alpha il 4rα on keratinocytes in murine models of leishmania major and schistosoma mansoni
topic Clinical Sciences and Immunology
url http://hdl.handle.net/11427/24890
work_keys_str_mv AT govendermelissa investigatingtheroleofil4il13signallingthroughtheil4receptoralphail4raonkeratinocytesinmurinemodelsofleishmaniamajorandschistosomamansoni

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