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Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector
Our studies on novel cyst wall proteins serendipitously led us to the discovery that cyst wall and vacuolar matrix protein MAG1, first identified a quarter of a century ago, functions as a secreted immunomodulatory effector. MAG1 is a dense granular protein that is found in the parasitophorous vacuo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262993/ https://www.ncbi.nlm.nih.gov/pubmed/34006649 http://dx.doi.org/10.1128/mBio.00603-21 |
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author | Tomita, Tadakimi Mukhopadhyay, Debanjan Han, Bing Yakubu, Rama Tu, Vincent Mayoral, Joshua Sugi, Tatsuki Ma, Yanfen Saeij, Jeroen P. J. Weiss, Louis M. |
author_facet | Tomita, Tadakimi Mukhopadhyay, Debanjan Han, Bing Yakubu, Rama Tu, Vincent Mayoral, Joshua Sugi, Tatsuki Ma, Yanfen Saeij, Jeroen P. J. Weiss, Louis M. |
author_sort | Tomita, Tadakimi |
collection | PubMed |
description | Our studies on novel cyst wall proteins serendipitously led us to the discovery that cyst wall and vacuolar matrix protein MAG1, first identified a quarter of a century ago, functions as a secreted immunomodulatory effector. MAG1 is a dense granular protein that is found in the parasitophorous vacuolar matrix in tachyzoite vacuoles and the cyst wall and matrix in bradyzoite vacuoles. In the current study, we demonstrated that MAG1 is secreted beyond the parasitophorous vacuole into the host cytosol in both tachyzoites and bradyzoites. Secretion of MAG1 gradually decreases as the parasitophorous vacuole matures, but prominent MAG1 puncta are present inside host cells even at 4 and 6 days following infection. During acute murine infection, Δmag1 parasites displayed significantly reduced virulence and dissemination. In the chronic stage of infection, Δmag1 parasites generated almost no brain cysts. To identify the mechanism behind the attenuated pathology seen with Δmag1 parasites, various immune responses were screened in vitro using bone marrow-derived macrophages (BMDM). Infection of BMDM with Δmag1 parasites induced a significant increase in interleukin 1β (IL-1β) secretion, which is a hallmark of inflammasome activation. Heterologous complementation of MAG1 in BMDM cells prevented this Δmag1 parasite-induced IL-1β release, indicating that secreted MAG1 in host cytosol dampens inflammasome activation. Furthermore, knocking out GRA15 (an inducer of IL-1β release) in Δmag1 parasites completely inhibited all IL-1β release by host cells following infection. These data suggest that MAG1 has a role as an immunomodulatory molecule and that by suppressing inflammasome activation, it would favor survival of the parasite and the establishment of latent infection. |
format | Online Article Text |
id | pubmed-8262993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-82629932021-07-23 Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector Tomita, Tadakimi Mukhopadhyay, Debanjan Han, Bing Yakubu, Rama Tu, Vincent Mayoral, Joshua Sugi, Tatsuki Ma, Yanfen Saeij, Jeroen P. J. Weiss, Louis M. mBio Research Article Our studies on novel cyst wall proteins serendipitously led us to the discovery that cyst wall and vacuolar matrix protein MAG1, first identified a quarter of a century ago, functions as a secreted immunomodulatory effector. MAG1 is a dense granular protein that is found in the parasitophorous vacuolar matrix in tachyzoite vacuoles and the cyst wall and matrix in bradyzoite vacuoles. In the current study, we demonstrated that MAG1 is secreted beyond the parasitophorous vacuole into the host cytosol in both tachyzoites and bradyzoites. Secretion of MAG1 gradually decreases as the parasitophorous vacuole matures, but prominent MAG1 puncta are present inside host cells even at 4 and 6 days following infection. During acute murine infection, Δmag1 parasites displayed significantly reduced virulence and dissemination. In the chronic stage of infection, Δmag1 parasites generated almost no brain cysts. To identify the mechanism behind the attenuated pathology seen with Δmag1 parasites, various immune responses were screened in vitro using bone marrow-derived macrophages (BMDM). Infection of BMDM with Δmag1 parasites induced a significant increase in interleukin 1β (IL-1β) secretion, which is a hallmark of inflammasome activation. Heterologous complementation of MAG1 in BMDM cells prevented this Δmag1 parasite-induced IL-1β release, indicating that secreted MAG1 in host cytosol dampens inflammasome activation. Furthermore, knocking out GRA15 (an inducer of IL-1β release) in Δmag1 parasites completely inhibited all IL-1β release by host cells following infection. These data suggest that MAG1 has a role as an immunomodulatory molecule and that by suppressing inflammasome activation, it would favor survival of the parasite and the establishment of latent infection. American Society for Microbiology 2021-05-18 /pmc/articles/PMC8262993/ /pubmed/34006649 http://dx.doi.org/10.1128/mBio.00603-21 Text en Copyright © 2021 Tomita 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 Tomita, Tadakimi Mukhopadhyay, Debanjan Han, Bing Yakubu, Rama Tu, Vincent Mayoral, Joshua Sugi, Tatsuki Ma, Yanfen Saeij, Jeroen P. J. Weiss, Louis M. Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title | Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title_full | Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title_fullStr | Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title_full_unstemmed | Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title_short | Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector |
title_sort | toxoplasma gondii matrix antigen 1 is a secreted immunomodulatory effector |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262993/ https://www.ncbi.nlm.nih.gov/pubmed/34006649 http://dx.doi.org/10.1128/mBio.00603-21 |
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