Transforming growth factor-ß as a therapeutic target for the cardiac damage of Chagas disease

Transforming growth factor beta (TGF-β) is deeply involved on the pathogenesis of Chagas disease. Our group has been investigating the participation of this pleiotropic cytokine in different aspects of Chagas disease over the last 20 years. Important observations have been made, such as: (i) the ability of Trypanosoma cruzi in activating latent TGF-β; (ii) the potential involvement of TGF-β pathway on T. cruzi invasion of host cells; (iii) association of TGF-β with parasite intracellular replication; (iv) cardiac fibrosis development and maintenance; (v) disruption of Connexin-43 plaque structures and (vi) inflammation and immune response. In this perspective article we intend to discuss the advances of the potential use of new therapies targeting TGF-β to treat the cardiac alterations of Chagas disease-affected patients.

Increased angiogenesis parallels cardiac tissue remodelling in experimental acute Trypanosoma cruzi infection

BACKGROUND Angiogenesis has been implicated in tissue injury in several noninfectious diseases, but its role in Chagas disease (CD) physiopathology is unclear. OBJECTIVES The present study aimed to investigate the effect of Trypanosoma cruzi infection on cardiac angiogenesis during the acute phase of experimental CD. METHODS The signalling pathway involved in blood vessel formation and cardiac remodelling was evaluated in Swiss Webster mice infected with the Y strain of T. cruzi. The levels of molecules involved in the regulation of angiogenesis, such as vascular endothelial growth factor-A (VEGF-A), Flk-1, phosphorylated extracellular-signal-regulated protein kinase (pERK), hypoxia-inducible factor-1α (HIF-1α), CD31, α-smooth muscle actin (α-SMA) and also the blood vessel growth were analysed during T. cruzi infection. Hearts were analysed using conventional histopathology, immunohistochemistry and western blotting. FINDINGS In this study, our data demonstrate that T. cruzi acute infection in mice induces exacerbated angiogenesis in the heart and parallels cardiac remodelling. In comparison with noninfected controls, the cardiac tissue of T. cruzi-infected mice presented higher levels of (i) HIF-1α, VEGF-A, Flk-1 and pERK; (ii) angiogenesis; (iii) α-SMA+ cells in the tissue; and (iv) collagen -1 deposition around blood vessels and infiltrating throughout the myocardium. MAIN CONCLUSIONS We observed cardiac angiogenesis during acute experimental T. cruzi infection parallels cardiac inflammation and remodelling.

Inhibition of Brazilian ZIKV strain replication in primary human placental chorionic cells and cervical cells treated with nitazoxanide

ABSTRACT Zika virus (ZIKV) infection during pregnancy is associated with a congenital syndrome. Although the virus can be detected in human placental tissue and sexual transmission has been verified, it is not clear how the virus reaches the fetus. Despite the emerging severity caused by ZIKV infection, no specific prophylactic and/or therapeutic treatment is available. The aim of the present study was to evaluate the effectiveness antiviral of nitazoxanide (NTZ) in two important congenital transmission targets: (i) a primary culture of human placental chorionic cells, and (ii) human cervical epithelial cells (C33-A) infected with Brazilian ZIKV strain. Initially, NTZ activity was screened in ZIKV infected Vero cells under different treatment regimens with non-toxic drug concentrations for 48 h. Antiviral effect was found only when the treatment was carried out after the viral inoculum. A strong effect against the dengue virus serotype 2 (DENV-2) was also observed suggesting the possibility of treating other Flaviviruses. Additionally, it was shown that the treatment did not reduce the production of infectious viruses in insect cells (C6/36) infected with ZIKV, indicating that the activity of this drug is also related to host factors. Importantly, we demonstrated that NTZ treatment in chorionic and cervical cells caused a reduction of infected cells in a dose-dependent manner and decreased viral loads in up to 2 logs. Pre-clinical in vitro testing evidenced excellent therapeutic response of infected chorionic and cervical cells and point to future NTZ activity investigation in ZIKV congenital transmission models with the perspective of possible repurposing of NTZ to treat Zika fever, especially in pregnant women.

Fisiopatologia da fibrose cardíaca chagásica: papel de TGF-Beta / Physiopathology of fibrosis chagasic cardiac: TGF-Beta paper

A miocardiopatia crônica é uma das principais manifestações associadas à morbidade na doença de Chagas, sendo possivelmente desencadeada pelas interações parasita-hospedeiro durante a fase aguda.A fibrose é uma das manifestações mais significativas da cardiopatia chagásica crônica e encontra-se associada com infiltrados inflamatórios e cardiomiócitos em degeneração.O TGF-beta é uma das principais citocinas envolvidas na regulação da formação e degradação de matriz extracelular e,portanto, dos processos fibróticos.Neste trabalho focalizamos nossa atenção no possível papel do TGF-beta como agente indutor/regulador de manifestações da cardiopatia chagásica,especialmente a fibrose.Estudos realizados com pacientes cardiopatas chagásicos crônicos,nos apontam para uma relação de TGF-beta com o desenvolvimento da fibrose.Nossos resultados demonstram...também apresentavam intensa fibrose e alta atividade biológica de TGF-beta no coração.Além disso,descrevemos que células miocárdicas de pacientes ou de modelos experimentais submetidos aos efeitos de níveis elevados de TGF-beta sofrem alterações no padrão de distribuição de Cx43 que podem estar relacionadas ao comprometimento da condutividade elétrica no coração e conseqüente arritmia.Como o TGF-beta já havia sido descrito como molécula mediadora dos processos de invasão celular na infecção pelo T.cruzi,estudamos a capacidade deste parasita em ativar e captar o TGF-beta do hospedeiro.Observamos que o T.cruzi é capaz de ativar TGF-beta latente de forma dose-e temperatura-dependente. Esta capacidade de ativação de TGF-beta era observada pela presença direta de parasitas vivos e de seus extratos total e citosólico,por um fator possivelmente protéico ou lipídico.Além disso,observamos que formas amastigotas de T.cruzi captam e internalizam TGF-beta do hospedeiro,estocando-o,para liberação no momento da diferenciação para tripomastigotas,o que evidencia um novo papel de TGF-beta no ciclo celular do parasita.O TGF-beta poderia estar sendo usado pelo parasita no momento de sinalizar a parada de proliferação e a diferenciação para tripomastigotas.Num contexto geral,a capacidade de T.cruzi para estocar e ativar TGF-beta poderia estar relacionada com diversos mecanismos diretos e indiretos atuantes no desenvolvimento da doença de Chagas.A manutenção de TGF-beta no tecido cardíaco pode estar diretamente relacionada com a formação de fibrose e com arritmias,além de sustentar a manutenção de uma carga residual de parasitas.