Differential Role of TGF-&amp;beta; in Extracellular Matrix Regulation during &lt;em&gt;Trypanosoma cruzi&amp;mdash;&lt;/em&gt;Host Cell Interaction

Silva, Tatiana Araújo; Ferreira, Luis Felipe de Carvalho; Pereira, Mirian Claudia de Souza; Calvet, Cláudia M.

doi:10.20944/preprints201905.0171.v1

Cited by 5 publications

(3 citation statements)

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“…In accordance with previous in vitro studies with cardiac fibroblasts [21] and colon cells [20], we detected an increase in p38 Y182 phosphorylation following chronic T. cruzi infection in mice (Fig 4K -4M). Interestingly, we also detected a significant decrease in singly phosphorylated p38 T180 peptides (Fig 4K).…”

Section: Plos Neglected Tropical Diseases (Fig 4d; S4 Tablesupporting

confidence: 92%

“…Second, we detected an increase in phosphorylation of NDRG2, a cell-stress related protein. Phosphorylation of p38 has been described for in vitro models of T. cruzi infection in colon cells (18) and cardiac fibroblasts [21]. p38 was also found increased during T. cruzi acute infection [100], but our data shows for the first time that p38 might be implicated in chronic Chagas cardiomyopathy in a model that displays clinical symptoms of heart failure.…”

Section: Discussionsupporting

confidence: 65%

“…The potential intracellular signaling pathways include c-Jun N-terminal kinase (JNK) [19] and p38 [20]. Recent reports from in vitro models of T. cruzi-host cell interaction demonstrated that cardiac fibroblasts display an increase in phosphorylation of p38 and c-Jun after infection [21]. Transcriptomic analysis showed that T. cruzi infection upregulates the JUNB gene and results in translocation of JunB to nuclei of primary human cardiomyocytes [19].…”

Section: Introductionmentioning

confidence: 99%

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways

et al. 2020

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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.

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Section: Plos Neglected Tropical Diseases (Fig 4d; S4 Tablesupporting

confidence: 92%

Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways

et al. 2020

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Bergamottin protects against LPS-induced endotoxic shock by regulating the NF-κB signaling pathway

2021

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Trypanosoma cruzi dysregulates expression profile of piRNAs in primary human cardiac fibroblasts during early infection phase

Rayford

Cooley²,

Strode³

et al. 2023

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi, the etiological agent of Chagas Disease, causes severe morbidity, mortality, and economic burden worldwide. Though originally endemic to Central and South America, globalization has led to increased parasite presence in most industrialized countries. About 40% of infected individuals will develop cardiovascular, neurological, and/or gastrointestinal pathologies. Accumulating evidence suggests that the parasite induces alterations in host gene expression profiles in order to facilitate infection and pathogenesis. The role of regulatory gene expression machinery during T. cruzi infection, particularly small noncoding RNAs, has yet to be elucidated. In this study, we aim to evaluate dysregulation of a class of sncRNAs called piRNAs during early phase of T. cruzi infection in primary human cardiac fibroblasts by RNA-Seq. We subsequently performed in silico analysis to predict piRNA-mRNA interactions. We validated the expression of these selected piRNAs and their targets during early parasite infection phase by stem loop qPCR and qPCR, respectively. We found about 26,496,863 clean reads (92.72%) which mapped to the human reference genome. During parasite challenge, 441 unique piRNAs were differentially expressed. Of these differentially expressed piRNAs, 29 were known and 412 were novel. In silico analysis showed several of these piRNAs were computationally predicted to target and potentially regulate expression of genes including SMAD2, EGR1, ICAM1, CX3CL1, and CXCR2, which have been implicated in parasite infection, pathogenesis, and various cardiomyopathies. Further evaluation of the function of these individual piRNAs in gene regulation and expression will enhance our understanding of early molecular mechanisms contributing to infection and pathogenesis. Our findings here suggest that piRNAs play important roles in infectious disease pathogenesis and can serve as potential biomarkers and therapeutic targets.

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Differential Role of TGF-β in Extracellular Matrix Regulation during <em>Trypanosoma cruzi—</em>Host Cell Interaction

Cited by 5 publications

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways

Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways

Bergamottin protects against LPS-induced endotoxic shock by regulating the NF-κB signaling pathway

Trypanosoma cruzi dysregulates expression profile of piRNAs in primary human cardiac fibroblasts during early infection phase

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