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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2023
Materias:
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.
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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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