Trypanosoma cruzi Promotes Transcriptomic Remodeling of the JAK/STAT Signaling and Cell Cycle Pathways in Myoblasts

Abstract

Chagas disease is responsible for more than 10,000 deaths per year and about 6 to 7 million infected people worldwide. In its chronic stage, patients can develop mega-colon, mega-esophagus, and cardiomyopathy. Differences in clinical outcomes may be determined, in part, by the genetic background of the parasite that causes Chagas disease. Trypanosoma cruzi has a high genetic diversity, and each group of strains may elicit specific pathological responses in the host. Conflicting results have been reported in studies using various combinations of mammalian host-T. cruzi strains. We previously profiled the transcriptomic signatures resulting from infection of L6E9 rat myoblasts with four reference strains of T. cruzi (Brazil, CL, Y, and Tulahuen). The four strains induced similar overall gene expression alterations in the myoblasts, although only 21 genes were equally affected by all strains. Cardiotrophin-like cytokine factor 1 (Clcf1) was one of the genes found to be consistently upregulated by the infection with all four strains of T. cruzi. This cytokine is a member of the interleukin-6 family that binds to glycoprotein 130 receptor and activates the JAK/STAT signaling pathway, which may lead to muscle cell hypertrophy. Another commonly upregulated gene was tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta (Ywhaq, 14-3-3 protein), present in the Cell Cycle Pathway. In the present work, we reanalyzed our previous microarray dataset, aiming at understanding in more details the transcriptomic impact that each strain has on JAK/STAT signaling and Cell Cycle pathways. Using Pearson correlation analysis between the expression levels of gene pairs in biological replicas from each pathway, we determined the coordination between such pairs in each experimental condition and the predicted protein interactions between the significantly altered genes by each strain. We found that although these highlighted genes were similarly affected by all four strains, the downstream genes or their interaction partners Nisimura et al. Transcriptomic Profiling of T. cruzi Infection were not necessarily equally affected, thus reinforcing the idea of the role of parasite background on host cell transcriptome. These new analyses provide further evidence to the mechanistic understanding of how distinct T. cruzi strains lead to diverse remodeling of host cell transcriptome.

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy

“…Transcriptome profiling have been performed in heart samples of patients ( Cunha-Neto et al., 2005 ; Deng et al., 2013 ) and mice ( Mukherjee et al., 2003 ; Soares et al., 2010 ) with CCC, and proteomic studies have been done using collected samples obtained by in vivo or in vitro experimental studies ( Hennig et al., 2019 ; Nisimura et al., 2020 ; Wozniak et al., 2020 ). However, these studies focused on the global expression profiling of the affected heart, and specific immune response gene profiling, specially upon therapy, has not been done to date.…”

Modulation of the Host Nuclear Compartment by Trypanosoma cruzi Uncovers Effects on Host Transcription and Splicing Machinery

“…Besides the difference in their genetic markers, these two strains lead to different remodeling of the host cell transcriptome in infected myoblasts. Tulahuen strain has significant negative regulation of genes related to RNA splicing than in strain Y ( Nisimura et al., 2020 ). This may be an indication of the reason for the decrease in hnRNP A1 in a longer time window in LLC-MK2 cells infected ( Figure 2B ) with the Tulahuen strain ( Figure S4B ).…”

Trypanosoma cruzi Dysregulates piRNAs Computationally Predicted to Target IL-6 Signaling Molecules During Early Infection of Primary Human Cardiac Fibroblasts

“…Primary human cardiac myocytes and fibroblasts constitute good models to study how the parasite can dysregulate the expression of genes and host immune signaling pathways, potentially contributing to T. cruzi pathogenesis. We and others showed that the parasite dysregulates host transcription, including the miRNA expression profile through unknown mechanisms ( 35 41 48 49 50 51 ). We and others also showed that the parasite increased the expression of host transcription factors and immune molecules that facilitate infection and play roles in fibrotic responses through unknown mechanisms ( 6 35 52 53 54 55 ).…”