RESUMEN
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), ß-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/ß-catenin pathway's target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/ß-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 ß-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.
Asunto(s)
Enfermedad de Chagas/inmunología , Interacciones Huésped-Parásitos/inmunología , Macrófagos/inmunología , Trypanosoma cruzi/inmunología , Vía de Señalización Wnt/inmunología , Animales , Línea Celular , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/mortalidad , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Humanos , Macrófagos/parasitología , Ratones , Ratones Endogámicos C57BL , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
A native bacterial strain with high capability for Cr (VI) removal was isolated from tannery sediments located in Elena (Córdoba Province, Argentina). The strain was characterized by amplification of 16S rRNA gene and identified as Serratia sp. C8. It was able to efficiently remove different Cr (VI) concentrations in a wide range of pHs and temperatures. The addition of different carbon sources as well as initial inoculum concentration were analyzed, demonstrating that Serratia sp. C8 could reduce 80 % of 20 mg/L Cr (VI) in a medium containing glucose 1 g/L, at pH 6-7 and 28 °C as optimal conditions, using 5 % inoculum concentration. The mechanisms involved in Cr (VI) removal were also evaluated. The strain was capable of biosorpting around 7.5-8.5 % of 20 mg/L Cr on its cell surface and to reduce Cr (VI). In addition, approximately a 54 and 46 % of total Cr was detected in the biomass and in the culture medium, respectively, and in the culture medium, Cr (III) was the predominant species. In conclusion, Serratia sp. C8 removed Cr (VI) and the mechanisms involved in decreasing order of contribution were as follows: reduction catalyzed by intracellular enzymes, accumulation into the cells, and biosorption to the microbial biomass. This strain could be a suitable microorganism for Cr (VI) bioremediation of tannery sediments and effluents or even for other environments contaminated with Cr.