Role of cyclooxygenase-2 in Trypanosoma cruzisurvival in the early stages of parasite host-cell interaction

Chagas disease, caused by the intracellular protozoan Trypanosoma cruzi, is a serious health problem in Latin America. During this parasitic infection, the heart is one of the major organs affected. The pathogenesis of tissue remodelling, particularly regarding cardiomyocyte behaviour after parasite infection and the molecular mechanisms that occur immediately following parasite entry into host cells are not yet completely understood. When cells are infected with T. cruzi, they develop an inflammatory response, in which cyclooxygenase-2 (COX-2) catalyses rate-limiting steps in the arachidonic acid pathway. However, how the parasite interaction modulates COX-2 activity is poorly understood. In this study, the H9c2 cell line was used as our model and we investigated cellular and biochemical aspects during the initial 48 h of parasitic infection. Oscillatory activity of COX-2 was observed, which correlated with the control of the pro-inflammatory environment in infected cells. Interestingly, subcellular trafficking was also verified, correlated with the control of Cox-2 mRNA or the activated COX-2 protein in cells, which is directly connected with the assemble of stress granules structures. Our collective findings suggest that in the very early stage of the T. cruzi-host cell interaction, the parasite is able to modulate the cellular metabolism in order to survives.

Angiostrongylus cantonensis infection in molluscs in the municipality of São Gonçalo, a metropolitan area of Rio de Janeiro, Brazil: role of the invasive species Achatina fulica in parasite transmission dynamics

The aim of this study was to analyse the infection dynamics ofAngiostrongylus cantonensisin its possible intermediate hosts over two years in an urban area in the state of Rio de Janeiro where the presence ofA. cantonensis had been previously recorded in molluscs. Four of the seven mollusc species found in the study were exotic.Bradybaena similariswas the most abundant, followed byAchatina fulica, Streptaxissp., Subulina octona, Bulimulus tenuissimus, Sarasinula linguaeformisand Leptinaria unilamellata. Only A. fulicaand B. similariswere parasitised by A. cantonensis and both presented co-infection with other helminths. The prevalence of A. cantonensisin A. fulicawas more than 50% throughout the study. There was an inverse correlation between the population size ofA. fulicaand the prevalence of A. cantonensisand abundance of the latter was negatively related to rainfall. The overall prevalence of A. cantonensisin B. similariswas 24.6%. A. fulicawas the most important intermediary host of A. cantonensisin the studied area andB. similariswas secondary in importance for A. cantonensistransmission dynamics.

Infeccoes de transmissao vertical em material abortivo e sangue com enfase em Toxoplasmose gondii

OBJETIVO: Analisar os resultados sorológicos, anatomopatológicos e parasitológicos de material abortivo para infecções com risco de transmissão vertical, com ênfase na toxoplasmose. MÉTODOS: Foi realizado um estudo coorte-transversal tratando da prevalência das doenças infectoparasitárias. Participaram da pesquisa 105 mulheres que sofreram aborto espontâneo completo e/ou incompleto; elas foram entrevistadas por meio de um questionário, e foram coletadas amostras de sangue e material abortivo. Foram realizados testes imunológicos para toxoplasmose, doença de Chagas, rubéola, citomegalovírus e sífilis e análise anatomopatológica nos restos ovulares. RESULTADOS: 55% das mulheres tinham entre 20 e 30 anos de idade. A maioria (68%) apresentou idade gestacional entre a 7ª e a 14ª semanas. 54,3% das mulheres tinham o ensino médio completo ou incompleto. Pela análise da sorologia, a infecção com risco de transmissão vertical mais frequente foi o citomegalovírus (CMV) com 97,1% de positividade, e em seguida a rubéola, com 95,2%. A toxoplasmose teve um percentual de 54,3%, a doença de Chagas, de 1,9% e a sífilis, de 0,95%. A análise dos laudos de biópsia demonstrou que 63,1% apresentaram inflamação e 34%, ausência de inflamação. Das análises sorológica, anatomopatológica e parasitológica das 105 mulheres, 57 foram soropositivas para T. gondii, e nenhuma teve resultado positivo para a Reação em Cadeia da Polimerase (PCR) e para inoculação em camundongos. CONCLUSÕES: A prevalência de doenças com risco de transmissão congênita nas mulheres com abortamento espontâneo é importante, sendo necessárias pesquisas visando esclarecer a etiologia do aborto.

Involvement of the actin cytoskeleton and p21rho-family GTPases in the pathogenesis of the human protozoan parasite Entamoeba histolytica

It has been estimated that infection with the enteric protozoan parasite Entamoeba histolytica kills more than 50,000 people a year. Central to the pathogenesis of this organism is its ability to directly lyse host cells and cause tissue destruction. Amebic lesions show evidence of cell lysis, tissue necrosis, and damage to the extracellular matrix. The specific molecular mechanisms by which these events are initiated, transmitted, and effected are just beginning to be uncovered. In this article we review what is known about host cell adherence and contact-dependent cytolysis. We cover the involvement of the actin cytoskeleton and small GTP-binding proteins of the p21rho-family in the process of cell killing and phagocytosis, and also look at how amebic interactions with molecules of the extracellular matrix contribute to its cytopathic effects.

Apoptosis in parasites and parasite-induced apoptosis in the host immune system: a new approach to parasitic diseases

Apoptosis, a form of programmed cell death (PCD), has been described as essential for normal organogenesis and tissue development, as well as for the proper function of cell-renewal systems in adult organisms. Apoptosis is also pivotal in the pathogenesis of several different diseases. In this paper we discuss, from two different points of view, the role of apoptosis in parasitic diseases. The description of apoptotic death in three different species of heteroxenic trypanosomatids is reviewed, and considerations on the phylogenesis of apoptosis and on the eventual role of PCD on their mechanism of pathogenesis are made. From a different perspective, an increasing body of evidence is making clear that regulation of host cell apoptosis is an important factor on the definition of a host-pathogen interaction. As an example, the molecular mechanisms by which Trypanosoma cruzi is able to induce apoptosis in immunocompetent cells, in a murine model of Chagas' disease, and the consequences of this phenomenon on the outcome of the experimental disease are discussed.

Detection of specific IgE antibodies in parasite diseases

Activation of Th1 or Th2 cells is associated with production of specific immunoglobulin isotypes, offering the opportunity to use antibody measurement for evaluation of T cell function. Schistosomiasis and visceral leishmaniasis are diseases associated with Th2 activation. However, an IgE response is not always detected in these patients. In the present study we evaluated specific IgE antibodies to S. mansoni and L. chagasi antigens by ELISA after depletion of serum IgG with protein G immobilized on Sepharose beads or RF-absorbent (purified sheep IgG antibodies anti-human IgG). In schistosomiasis patients, specific IgE to SWAP antigen was demonstrable in only 10 of 21 patients (48%) (mean absorbance ± SD = 0.102 ± 0.195) when unabsorbed serum was used. Depletion of IgG with protein G increased the number of specific IgE-positive tests to 13 (62%) and the use of RF-absorbent increased the number of positive results to 20 (95%) (mean absorbances ± SD = 0.303 ± 0.455 and 0.374 ± 0.477, respectively). Specific IgE anti-L. chagasi antibodies were not detected in unabsorbed serum from visceral leishmaniasis patients. When IgG was depleted with protein G, IgE antibodies were detected in only 3 (11%) of 27 patients, and the use of RF-absorbent permitted the detection of this isotype in all 27 visceral leishmaniasis sera tested (mean absorbance ± SD = 0.104 ± 0.03). These data show that the presence of IgG antibodies may prevent the detection of a specific IgE response in these parasite diseases. RF-absorbent, a reagent that blocks IgG-binding sites and also removes rheumatoid factor, was more efficient than protein G for the demonstration of specific IgE antibodies.

Interruption of the blood-stage cycle of the malaria parasite, Plasmodium chabaudi, by protein tyrosine kinase inhibitors

Malaria is a devastating disease caused by a unicellular protozoan, Plasmodium, which affects 3.7 million people every year. Resistance of the parasite to classical treatments such as chloroquine requires the development of new drugs. To gain insight into the mechanisms that control Plasmodium cell cycle, we have examined the effects of kinase inhibitors on the blood-stage cycle of the rodent malaria parasite, Plasmodium chabaudi. In vitro incubation of red blood cells for 17 h at 37ºC with the inhibitors led to a decrease in the percent of infected cells, compared to control treatment, as follows: genistein (200 µM - 75%), staurosporine (1 µM - 58%), R03 (1 µM - 75%), and tyrphostins B44 (100 µM - 66%) and B46 (100 µM - 68%). All these treatments were shown to retard or prevent maturation of the intraerythrocytic parasites. The diverse concentration ranges at which these inhibitors exert their effects give a clue as to the types of signals that initiate the transitions between the different developmental stages of the parasite. The present data support our hypothesis that the maturation of the intraerythrocytic cycle of malaria parasites requires phosphorylation. In this respect, we have recently reported a high Ca2+ microenvironment surrounding the parasite within red blood cells. Several kinase activities are modulated by Ca2+. The molecular identification of the targets of these kinases could provide new strategies against malaria.

Vitamin B1 and B6 in the malaria parasite: requisite or dispensable?

Vitamins are essential compounds mainly involved in acting as enzyme co-factors or in response to oxidative stress. In the last two years it became apparent that apicomplexan parasites are able to generate B vitamers such as vitamin B1 and B6 de novo. The biosynthesis pathways responsible for vitamin generation are considered as drug targets, since both provide a high degree of selectivity due to their absence in the human host. This report updates the current knowledge about vitamin B1 and B6 biosynthesis in malaria and other apicomplexan parasites. Owing to the urgent need for novel antimalarials, the significance of the biosynthesis and salvage of these vitamins is critically discussed in terms of parasite survival and their exploitation for drug development.

Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals.