CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
T. CRUZI INFECTION INDUCES FIRST WNT/beta-CATENIN AND THEN WNT/CA+2 PATHWAYS ACTIVATION IN MACROPHAGES WHICH FAVOUR THE PARASITE REPLICATION.
Autor/es:
FOZZATTI, LAURA; VOLPINI, XIMENA; INSFRÁN, CONSTANZA; AMBROSIO, LAURA; MOTRÁN, CRISTINA
Lugar:
Cancun
Reunión:
Congreso; XII Congress of the Latin American Association of Immunology (ALAI) & XXIII Congress of the Mexican Society of Immunology (SMI).; 2018
Institución organizadora:
Latin American Association of Immunology (ALAI)
Resumen:
Chagas´ disease, caused by the protozoan parasite Trypanosoma cruzi, represents a major cause of heart disease and cardiovascular-related deaths in endemic areas, and causes a significant economic burden on the affected countries. Approximately 8 million people are infected with T. cruzi in Central and South America, and at least 120 million are at risk of infection. Currently, 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.During the infection with T. cruzi, both a strong inflammatory and an efficient regulatory response are essential to restrict parasite replication and prevent immunopathology. At the acute phase of infection, macrophages can act as "host" cells for the parasites and, in turn, as effector cells in the early anti-parasitic immune response. In these cells, parasite replication can be either inhibited or favoured leading to dissemination to other sites within the body. Thus, the targeting of specific signaling pathways could modulate macrophage response to restrict parasite replication and instruct an appropriate adaptive response.Recently, it has become apparent that Wnt signaling pathway exerts immunomodulatory functions during inflammation and infection. We have 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. We have observed that early after T. cruzi infection of bone marrow derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzed receptors as well as target genes of Wnt/-catenin pathway were up-regulated, 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 IDO activity and by down-regulating 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 the present study we reported a new signaling pathway that is activated by the interaction between T. cruzi and host innate immunity, establishing a new conceptual framework for the development of new therapies.