Abstract
During the acute phase of Trypanosoma cruzi infection, macrophages can act as host cells for the parasites as well as effector cells in the early anti-parasitic immune response. Thus, the targeting of specific signaling pathways could modulate macrophages response to restrict parasite replication and instruct an appropriate adaptive response. Recently, it has become evident that Wnt signaling has immunomodulatory functions during inflammation and infection. Here, we tested the hypothesis that during T. cruzi infection, the activation of Wnt signaling pathway in macrophages plays a role in modulating the inflammatory/tolerogenic response and therefore regulating the control of parasite replication. In this report, we show that early after T. cruzi infection of bone marrow-derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/β-catenin pathway’s target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/β-catenin pathway and then activating the Wnt/Ca+2 pathway. Wnt signaling pathway activation was critical to sustain the parasite’s replication in BMM; since the treatments with specific inhibitors of β-catenin transcriptional activation or Wnt proteins secretion limited the parasite replication. Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against T. cruzi by inducing the production of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase activity and by downregulating arginase activity. Likewise, in vivo pharmacological inhibition of the Wnts’ interaction with its receptors controlled the parasite replication and improved the survival of lethally infected mice. It is well established that T. cruzi infection activates a plethora of signaling pathways that ultimately regulate immune mediators to determine the modulation of a defined set of effector functions in macrophages. In this study, we have revealed a new signaling pathway that is activated by the interaction between protozoan parasites and host innate immunity, establishing a new conceptual framework for the development of new therapies.
Highlights
Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, represents a major cause of heart disease and cardiovascularrelated deaths in endemic areas and causes a significant economic burden on the affected countries
In T. cruzi-infected B6 mice the main target organ of pathological inflammatory response is the liver, and not the heart as in infected human patients, we performed the experiments in B6 mice to evaluate both parasite replication and inflammatory pathology
To study whether experimental infection with T. cruzi induces the production of Wnt pathway proteins, the expression of the most common inflammation-linked Wnt proteins such as Wnt3a and Wnt5a, and β-catenin was evaluated in spleen cells from infected B6 mice at different times pi
Summary
Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, represents a major cause of heart disease and cardiovascularrelated deaths in endemic areas and causes a significant economic burden on the affected countries. There are no vaccines available to prevent Chagas disease, and treatment options are limited to anti-parasitic drugs that are expensive, not well tolerated, and effective only during short periods of the acute phase [2]. During the acute phase of the infection macrophages represent an important target of Trypanosoma cruzi and these cells are central for the control of this pathogen. It has been reported that during the early phase of infection, the control T. cruzi parasitism is dependent on macrophage activation through toll-like receptors (TLRs) and their subsequent activation by pro-inflammatory cytokines. A better understanding of the cellular and molecular mechanisms that orchestrate the different signals that promote the effective macrophage activation (able to restrict parasite replication) followed by its opportune contraction to prevent immunopathology is mandatory to design improved therapeutic strategies
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