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Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection
Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is tho...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Company of Biologists Ltd
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399977/ https://www.ncbi.nlm.nih.gov/pubmed/37357611 http://dx.doi.org/10.1242/jcs.260809 |
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author | Ullah, Imran Barrie, Umaru Kernen, Rebecca M. Mamula, Emily T. Khuong, Francis Tho Huu Booshehri, Laela M. Rhodes, Emma L. Bradford, James M. Datta, Arani Wetzel, Dawn M. |
author_facet | Ullah, Imran Barrie, Umaru Kernen, Rebecca M. Mamula, Emily T. Khuong, Francis Tho Huu Booshehri, Laela M. Rhodes, Emma L. Bradford, James M. Datta, Arani Wetzel, Dawn M. |
author_sort | Ullah, Imran |
collection | PubMed |
description | Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is thought to be mainly host cell driven, not parasite driven. Our previous work indicates that host Src- and Abl-family kinases facilitate Leishmania entry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here, we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake of Leishmania promastigotes and amastigotes. A Src-family kinase–Abl-family kinase–SYK signaling cascade induces Leishmania amastigote internalization. Finally, lesion size and parasite burden during Leishmania infection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximal Leishmania uptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents. |
format | Online Article Text |
id | pubmed-10399977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-103999772023-08-04 Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection Ullah, Imran Barrie, Umaru Kernen, Rebecca M. Mamula, Emily T. Khuong, Francis Tho Huu Booshehri, Laela M. Rhodes, Emma L. Bradford, James M. Datta, Arani Wetzel, Dawn M. J Cell Sci Research Article Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is thought to be mainly host cell driven, not parasite driven. Our previous work indicates that host Src- and Abl-family kinases facilitate Leishmania entry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here, we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake of Leishmania promastigotes and amastigotes. A Src-family kinase–Abl-family kinase–SYK signaling cascade induces Leishmania amastigote internalization. Finally, lesion size and parasite burden during Leishmania infection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximal Leishmania uptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents. The Company of Biologists Ltd 2023-07-28 /pmc/articles/PMC10399977/ /pubmed/37357611 http://dx.doi.org/10.1242/jcs.260809 Text en © 2023. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Ullah, Imran Barrie, Umaru Kernen, Rebecca M. Mamula, Emily T. Khuong, Francis Tho Huu Booshehri, Laela M. Rhodes, Emma L. Bradford, James M. Datta, Arani Wetzel, Dawn M. Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title | Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title_full | Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title_fullStr | Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title_full_unstemmed | Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title_short | Src- and Abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and Leishmania infection |
title_sort | src- and abl-family kinases activate spleen tyrosine kinase to maximize phagocytosis and leishmania infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399977/ https://www.ncbi.nlm.nih.gov/pubmed/37357611 http://dx.doi.org/10.1242/jcs.260809 |
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