Trypanosoma cruzi Exploits Wnt Signaling Pathway to Promote Its Intracellular Replication in Macrophages

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.

Wnt Signalling Orchestrates the Immune Response and Cardiac Damage DuringTrypanosoma cruziInfection

“…To evaluate the effect of Wnt signalling inhibition on parasitaemia and heart parasitism in an animal model of chronic Chagas'disease, BALB/c mice were infected with a non-lethal doses of Tulahuen strain of T. cruzi and treated with IWP-L6 (IWP-L6 mice) or vehicle (Control mice) at days 5;8;11 and 14 p.i. Similar to that observed in B6 mice (29), IWP-L6 mice showed lower parasitaemia and heart parasite load than Control mice in the acute phase of the infection. ( Figure 1A and B).…”

“…On the other hand, it is important to take into account that not only immune system cells and their products but also many other signalling systems and complex cellular interactions between recruited and cardiac cells (myocytes, fibroblasts, endothelial cells, smooth muscle cells, epicardial cells) can participate in the damage and repair processes that occur after the parasite-or inflammation-induced injury. Thus, during T. cruzi infection, the Wnt signalling system would not only be involved in modulating Mo phenotype and function, as we have previously demonstrated (29), but could also play a role in orchestrating the cardiac damage that follows a parasite infection as it has been shown in ischemia or hypertrophy (reviewed by Deb, A (43)). Here, we show evidences that inhibition of Wnt was able to (29), we speculate that this treatment contributes to shift the characteristic Th2-type immune response developed by BALB/c mice to a Th1-type.…”

Downregulation of Dickkopf-1 Augments the Therapeutic Effects of Endometrial Regenerative Cells on Experimental Colitis

“…Next, we carried out the following experiments in vivo and found that in DKK1 low -ERC (ERC pretreated with IL-1β) group, clinical characters and pathological manifestations of colitis were strikingly ameliorated, in which the immune-regulatory effects of ERCs may be enhanced by low DKK1 production, as a result of Wnt/β-catenin pathway being activated [34,47]. Comparing with that in DKK1 high -ERC (ERC pretreated with GC) group, we con rmed that DKK1 plays a vital role in affecting therapeutic function of ERCs on experimental colitis.…”

mTORC1 Prevents Epithelial Damage During Inflammation and Inhibits Colitis-Associated Colorectal Cancer Development

“…The mechanism underlying such process needs to be further investigated but our results suggest that transactivation of β-catenin in epithelial cells and in macrophages could play an important role. Accordingly, β-catenin enhances intestinal epithelial cell proliferation [40] and in the absence of E-cadherin, a well-known β-catenin inhibitor, necrosis and anoikis sparked in IECs during colitis [41] , [42] . Such process could be directly related to the hyperproliferation induced by β-catenin.…”