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Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse

Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely t...

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Autores principales: Rudzki, Elizabeth N., Ander, Stephanie E., Coombs, Rachel S., Alrubaye, Hisham S., Cabo, Leah F., Blank, Matthew L., Gutiérrez-Melo, Nicolás, Dubey, J. P., Coyne, Carolyn B., Boyle, Jon P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593671/
https://www.ncbi.nlm.nih.gov/pubmed/34781732
http://dx.doi.org/10.1128/mBio.01591-21
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author Rudzki, Elizabeth N.
Ander, Stephanie E.
Coombs, Rachel S.
Alrubaye, Hisham S.
Cabo, Leah F.
Blank, Matthew L.
Gutiérrez-Melo, Nicolás
Dubey, J. P.
Coyne, Carolyn B.
Boyle, Jon P.
author_facet Rudzki, Elizabeth N.
Ander, Stephanie E.
Coombs, Rachel S.
Alrubaye, Hisham S.
Cabo, Leah F.
Blank, Matthew L.
Gutiérrez-Melo, Nicolás
Dubey, J. P.
Coyne, Carolyn B.
Boyle, Jon P.
author_sort Rudzki, Elizabeth N.
collection PubMed
description Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell, where it localizes to the nucleus, and deletion of the GRA28 gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall, these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells and show a clear impact of this immunomodulation on infection outcome.
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spelling pubmed-85936712021-12-02 Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse Rudzki, Elizabeth N. Ander, Stephanie E. Coombs, Rachel S. Alrubaye, Hisham S. Cabo, Leah F. Blank, Matthew L. Gutiérrez-Melo, Nicolás Dubey, J. P. Coyne, Carolyn B. Boyle, Jon P. mBio Research Article Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell, where it localizes to the nucleus, and deletion of the GRA28 gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall, these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells and show a clear impact of this immunomodulation on infection outcome. American Society for Microbiology 2021-11-16 /pmc/articles/PMC8593671/ /pubmed/34781732 http://dx.doi.org/10.1128/mBio.01591-21 Text en Copyright © 2021 Rudzki et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Rudzki, Elizabeth N.
Ander, Stephanie E.
Coombs, Rachel S.
Alrubaye, Hisham S.
Cabo, Leah F.
Blank, Matthew L.
Gutiérrez-Melo, Nicolás
Dubey, J. P.
Coyne, Carolyn B.
Boyle, Jon P.
Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title_full Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title_fullStr Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title_full_unstemmed Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title_short Toxoplasma gondii GRA28 Is Required for Placenta-Specific Induction of the Regulatory Chemokine CCL22 in Human and Mouse
title_sort toxoplasma gondii gra28 is required for placenta-specific induction of the regulatory chemokine ccl22 in human and mouse
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593671/
https://www.ncbi.nlm.nih.gov/pubmed/34781732
http://dx.doi.org/10.1128/mBio.01591-21
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