Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.
Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most...
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ftdoajarticles:oai:doaj.org/article:2a60e80054e049599c289fcae6760c1f 2023-05-15T15:10:59+02:00 Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. Jacob M Wozniak Tatiana Araújo Silva Diane Thomas Jair L Siqueira-Neto James H McKerrow David J Gonzalez Claudia M Calvet 2020-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007980 https://doaj.org/article/2a60e80054e049599c289fcae6760c1f EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007980 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007980 https://doaj.org/article/2a60e80054e049599c289fcae6760c1f PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0007980 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007980 2022-12-31T07:36:44Z Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets. Article in Journal/Newspaper Arctic Human health Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 5 e0007980 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Jacob M Wozniak Tatiana Araújo Silva Diane Thomas Jair L Siqueira-Neto James H McKerrow David J Gonzalez Claudia M Calvet Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets. |
format |
Article in Journal/Newspaper |
author |
Jacob M Wozniak Tatiana Araújo Silva Diane Thomas Jair L Siqueira-Neto James H McKerrow David J Gonzalez Claudia M Calvet |
author_facet |
Jacob M Wozniak Tatiana Araújo Silva Diane Thomas Jair L Siqueira-Neto James H McKerrow David J Gonzalez Claudia M Calvet |
author_sort |
Jacob M Wozniak |
title |
Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
title_short |
Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
title_full |
Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
title_fullStr |
Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
title_full_unstemmed |
Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
title_sort |
molecular dissection of chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0007980 https://doaj.org/article/2a60e80054e049599c289fcae6760c1f |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic Human health |
genre_facet |
Arctic Human health |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0007980 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007980 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007980 https://doaj.org/article/2a60e80054e049599c289fcae6760c1f |
op_doi |
https://doi.org/10.1371/journal.pntd.0007980 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
5 |
container_start_page |
e0007980 |
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1766341907844169728 |