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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...

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Autores principales: Tomita, Tadakimi, Mukhopadhyay, Debanjan, Han, Bing, Yakubu, Rama, Tu, Vincent, Mayoral, Joshua, Sugi, Tatsuki, Ma, Yanfen, Saeij, Jeroen P. J., Weiss, Louis M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
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.
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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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