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Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii

Little is known about strategies used by pathogens to facilitate CNS invasion. Toxoplasma gondii reaches the CNS by circulating in blood within leukocytes or as extracellular tachyzoites. T. gondii induces EGFR signaling in vitro during invasion of mammalian cells. We examined the effects of endothe...

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Autores principales: Corcino, Yalitza Lopez, Portillo, Jose-Andres C., Subauste, Carlos S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345933/
https://www.ncbi.nlm.nih.gov/pubmed/30679495
http://dx.doi.org/10.1038/s41598-018-36724-2
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author Corcino, Yalitza Lopez
Portillo, Jose-Andres C.
Subauste, Carlos S.
author_facet Corcino, Yalitza Lopez
Portillo, Jose-Andres C.
Subauste, Carlos S.
author_sort Corcino, Yalitza Lopez
collection PubMed
description Little is known about strategies used by pathogens to facilitate CNS invasion. Toxoplasma gondii reaches the CNS by circulating in blood within leukocytes or as extracellular tachyzoites. T. gondii induces EGFR signaling in vitro during invasion of mammalian cells. We examined the effects of endothelial cell EGFR on CNS invasion. Transgenic mice whose endothelial cells expressed a dominant negative (DN) EGFR (inhibits EGFR signaling) exhibited diminished parasite load and histopathology in the brain and retina after T. gondii infection. I.V. administration of infected leukocytes or extracellular tachyzoites led to reduced parasite loads in mice with DN EGFR. This was not explained by enhanced immunity or reduced leukocyte recruitment. Endothelial cell infection is key for CNS invasion. Parasite foci in brain endothelial cells were reduced by DN EGFR. DN EGFR in these cells led to recruitment of the autophagy protein LC3 around T. gondii and spontaneous parasite killing dependent on the autophagy protein ULK1 and lysosomal enzymes. The autophagy inhibitor 3-MA prevented DN EGFR mice from exhibiting reduced CNS invasion. Altogether, EGFR is a novel regulator of T. gondii invasion of neural tissue, enhancing invasion likely by promoting survival of the parasite within endothelial cells.
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spelling pubmed-63459332019-01-29 Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii Corcino, Yalitza Lopez Portillo, Jose-Andres C. Subauste, Carlos S. Sci Rep Article Little is known about strategies used by pathogens to facilitate CNS invasion. Toxoplasma gondii reaches the CNS by circulating in blood within leukocytes or as extracellular tachyzoites. T. gondii induces EGFR signaling in vitro during invasion of mammalian cells. We examined the effects of endothelial cell EGFR on CNS invasion. Transgenic mice whose endothelial cells expressed a dominant negative (DN) EGFR (inhibits EGFR signaling) exhibited diminished parasite load and histopathology in the brain and retina after T. gondii infection. I.V. administration of infected leukocytes or extracellular tachyzoites led to reduced parasite loads in mice with DN EGFR. This was not explained by enhanced immunity or reduced leukocyte recruitment. Endothelial cell infection is key for CNS invasion. Parasite foci in brain endothelial cells were reduced by DN EGFR. DN EGFR in these cells led to recruitment of the autophagy protein LC3 around T. gondii and spontaneous parasite killing dependent on the autophagy protein ULK1 and lysosomal enzymes. The autophagy inhibitor 3-MA prevented DN EGFR mice from exhibiting reduced CNS invasion. Altogether, EGFR is a novel regulator of T. gondii invasion of neural tissue, enhancing invasion likely by promoting survival of the parasite within endothelial cells. Nature Publishing Group UK 2019-01-24 /pmc/articles/PMC6345933/ /pubmed/30679495 http://dx.doi.org/10.1038/s41598-018-36724-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Corcino, Yalitza Lopez
Portillo, Jose-Andres C.
Subauste, Carlos S.
Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title_full Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title_fullStr Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title_full_unstemmed Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title_short Epidermal growth factor receptor promotes cerebral and retinal invasion by Toxoplasma gondii
title_sort epidermal growth factor receptor promotes cerebral and retinal invasion by toxoplasma gondii
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345933/
https://www.ncbi.nlm.nih.gov/pubmed/30679495
http://dx.doi.org/10.1038/s41598-018-36724-2
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