Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways
| Autor: | James H. McKerrow, Tatiana Araújo Silva, Claudia M. Calvet, Jair L. Siqueira-Neto, Diane Thomas, David Gonzalez, Jacob M. Wozniak |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Chagas Cardiomyopathy
Proteomics 0301 basic medicine Proteome Cell Membranes RC955-962 Disease Biochemistry Infographics Mice 0302 clinical medicine Arctic medicine. Tropical medicine Medicine and Health Sciences Post-Translational Modification Phosphorylation Energy-Producing Organelles Protozoans Eukaryota Heart Mitochondria Infectious Diseases Female Anatomy Cellular Structures and Organelles Signal transduction Public aspects of medicine RA1-1270 Cardiomyopathies Graphs Research Article Neglected Tropical Diseases Signal Transduction Chagas disease Trypanosoma Computer and Information Sciences Trypanosoma cruzi 030231 tropical medicine Cardiology Bioenergetics Biology 03 medical and health sciences Parasitic Diseases medicine Animals Humans Chagas Disease Kinase activity Protozoan Infections Data Visualization Organisms Public Health Environmental and Occupational Health Biology and Life Sciences Proteins Membrane Proteins Cell Biology Tropical Diseases medicine.disease biology.organism_classification Parasitic Protozoans Mice Inbred C57BL 030104 developmental biology Membrane protein Immunology Cardiovascular Anatomy |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 14, Iss 5, p e0007980 (2020) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | 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. Author summary Chagas disease is a significant human health concern as it can cause severe cardiomyopathies in chronically infected patients. Due to the high morbidity associated with Chagasic cardiomyopathies, it is vital to investigate new treatment options. In this study, we use state-of-the-art techniques to interrogate the host signaling events induced by chronic Chagas disease in the primary affected organ, the heart. We identify proteins and phospho-sites significantly altered upon infection, predict activated and inhibited kinases, and link our findings to known drug targets. For the first time, this study provides insight into the in vivo host signaling responses to T. cruzi in the heart, uncovering pathways that can be validated for contributions to disease and suitability as drug targets. |
| Databáze: | OpenAIRE |
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