EarlyTrypanosoma cruziInfection Reprograms Human Epithelial Cells

Abstract

Trypanosoma cruzi, the causative agent of Chagas disease, has the peculiarity, when compared with other intracellular parasites, that it is able to invade almost any type of cell. This property makes Chagas a complex parasitic disease in terms of prophylaxis and therapeutics. The identification of key host cellular factors that play a role in the T. cruzi invasion is important for the understanding of disease pathogenesis. In Chagas disease, most of the focus is on the response of macrophages and cardiomyocytes, since they are responsible for host defenses and cardiac lesions, respectively. In the present work, we studied the early response to infection of T. cruzi in human epithelial cells, which constitute the first barrier for establishment of infection. These studies identified up to 1700 significantly altered genes regulated by the immediate infection. The global analysis indicates that cells are literally reprogrammed by T. cruzi, which affects cellular stress responses (neutrophil chemotaxis, DNA damage response), a great number of transcription factors (including the majority of NFκB family members), and host metabolism (cholesterol, fatty acids, and phospholipids). These results raise the possibility that early host cell reprogramming is exploited by the parasite to establish the initial infection and posterior systemic dissemination.

Notch receptor expression in Trypanosoma cruzi‐infected human umbilical vein endothelial cells treated with benznidazole or simvastatin revealed by microarray analysis

“…Although Castillo et al (2018) previously reported changes similar to those described in the present model, the number of downregulated genes was high compared with that observed by Chiribao et al (2014). That study found a high number of differentially expressed genes (1700) when the effect of infection on epithelial cells was analyzed.…”

“…Undoubtedly, T. cruzi infection produces significant changes in cellular gene expression, as shown in several reports (Manque et al, 2011; Chiribao et al, 2014; Li et al, 2016). These findings were also observed in our model, where 159 genes were upregulated and 242 were downregulated during the infection.…”

Old Yellow Enzyme from Trypanosoma cruzi Exhibits In Vivo Prostaglandin F2α Synthase Activity and Has a Key Role in Parasite Infection and Drug Susceptibility

“…Although disease pathogenesis remains unclear, it is well known that both parasite and host responses play relevant roles. Immediately after adhesion and during the initial stages of infection, Trypanosoma cruzi dramatically remodels host cell gene expression profile, with specific patterns on each cell type ( 1 , 2 ); B and T cell immunity also plays important roles both in the control and pathogenesis of the disease ( 3 , 4 ). The low or null parasite cardiac load in patients with chronic chagasic cardiomyopathy lead a discussion in the literature regarding the etiology of Chagas disease, where different factors such as T. cruzi strains, genetic background of the host, altered immune responses, and autoimmunity where associated with clinical outcomes of the disease [reviewed in Ref.…”

Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi‐Infected Mice

“…Consistent with the parasite load and leucocytes infiltrate, our results also indicated that animals treated with the highest doses of Sur exhibited high cardiac levels of TNF- α and IFN- γ , which are two effector molecules produced from the polarized Th1 immunological phenotype [ 43 , 44 ]. In addition to the direct leucocyte recruitment triggered by cytokines (e.g., TNF- α , IFN- γ ) and chemokines (e.g., MCP1, MIP-1 and 2) secreted in response to T. cruzi antigens, direct cardiomyocytolysis, and cell death induced by the continuous replication of amastigotes also contributes to leucocyte recruitment and activation [ 45 , 46 ]. There is evidence that high parasite load is closely correlated with intense immunological polarization to a Th1 phenotype, which is paradoxically implicated in antitrypanosomal defense and cardiac damage [ 19 , 26 , 44 ].…”