Trypanosoma cruzi: Role of δ-Amastin on Extracellular Amastigote Cell Invasion and Differentiation

Trypanosoma cruzi is a protozoan parasite that comprises different phylogenetic groups and is the causative agent of Chagas’ disease. Different T. cruzi strains present differences in infectivity in in vitro and in vivo experimental models, which are likely related to the expression of different virulence factors. Amastin is a surface glycoprotein abundantly expressed on the intracellular mammalian amastigote form of the parasite. In this study, we showed that a highly infective strain (G strain) of extracellular amastigote (EA) invasive forms expressed reduced RNA levels of amastin compared to a less infective strain (CL). The treatment of HeLa cells with recombinant δ-amastin reduced infectivity of EA forms. However, the ectopic expression of δ-amastin accelerated amastigote differentiation into trypomastigotes. Corroborating the virulence behavior in association with amastin expression, the EAs overexpressing amastin were precociously and robustly observed in the liver of susceptible mouse strains (A/JUnib), whereas parasitemia was never detected in in vivo assays. This is the first report on the regulatory role of amastin in the course of both in vitro and in vivo T. cruzi infection.     

A Recombinant Protein Based on Trypanosoma cruzi P21 Enhances Phagocytosis

Background

P21 is a secreted protein expressed in all developmental stages of Trypanosoma cruzi. The aim of this study was to determine the effect of the recombinant protein based on P21 (P21-His₆) on inflammatory macrophages during phagocytosis.

Findings

Our results showed that P21-His₆ acts as a phagocytosis inducer by binding to CXCR4 chemokine receptor and activating actin polymerization in a way dependent onthe PI3-kinase signaling pathway.

Conclusions

Thus, our results shed light on the notion that native P21 is a component related to T. cruzi evasion from the immune response and that CXCR4 may be involved in phagocytosis. P21-His₆ represents an important experimental control tool to study phagocytosis signaling pathways of different intracellular parasites and particles.     

Fexinidazole: A Potential New Drug Candidate for Chagas Disease

Background

New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi.

Methods and Findings

We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses.

Conclusions

Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD.     

Transparent mediation-based access to multiple yeast data sources using an ontology driven interface

BACKGROUND: Saccharomyces cerevisiae is recognized as a model system representing a simple eukaryote whose genome can be easily manipulated. Information solicited by scientists on its biological entities (Proteins, Genes, RNAs...) is scattered within several data sources like SGD, Yeastract, CYGD-MIPS, BioGrid, PhosphoGrid, etc. Because of the heterogeneity of these sources, querying them separately and then manually combining the returned results is a complex and time-consuming task for biologists most of whom are not bioinformatics expert. It also reduces and limits the use that can be made on the available data. RESULTS: To provide transparent and simultaneous access to yeast sources, we have developed YeastMed: an XML and mediator-based system. In this paper, we present our approach in developing this system which takes advantage of SB-KOM to perform the query transformation needed and a set of Data Services to reach the integrated data sources. The system is composed of a set of modules that depend heavily on XML and Semantic Web technologies. User queries are expressed in terms of a domain ontology through a simple form-based web interface. CONCLUSIONS: YeastMed is the first mediation-based system specific for integrating yeast data sources. It was conceived mainly to help biologists to find simultaneously relevant data from multiple data sources. It has a biologist-friendly interface easy to use. The system is available at http://www.khaos.uma.es/yeastmed/.     

Rhodolith beds are major CaCO3 bio-factories in the tropical South West Atlantic

Rhodoliths are nodules of non-geniculate coralline algae that occur in shallow waters (<150 m depth) subjected to episodic disturbance. Rhodolith beds stand with kelp beds, seagrass meadows, and coralline algal reefs as one of the world's four largest macrophyte-dominated benthic communities. Geographic distribution of rhodolith beds is discontinuous, with large concentrations off Japan, Australia and the Gulf of California, as well as in the Mediterranean, North Atlantic, eastern Caribbean and Brazil. Although there are major gaps in terms of seabed habitat mapping, the largest rhodolith beds are purported to occur off Brazil, where these communities are recorded across a wide latitudinal range (2°N-27°S). To quantify their extent, we carried out an inter-reefal seabed habitat survey on the Abrolhos Shelf (16°50'-19°45'S) off eastern Brazil, and confirmed the most expansive and contiguous rhodolith bed in the world, covering about 20,900 km(2). Distribution, extent, composition and structure of this bed were assessed with side scan sonar, remotely operated vehicles, and SCUBA. The mean rate of CaCO(3) production was estimated from in situ growth assays at 1.07 kg m(-2) yr(-1), with a total production rate of 0.025 Gt yr(-1), comparable to those of the world's largest biogenic CaCO(3) deposits. These gigantic rhodolith beds, of areal extent equivalent to the Great Barrier Reef, Australia, are a critical, yet poorly understood component of the tropical South Atlantic Ocean. Based on the relatively high vulnerability of coralline algae to ocean acidification, these beds are likely to experience a profound restructuring in the coming decades.     

Trypanosoma cruzi: acute and long-term infection in the vertebrate host can modify the response to benznidazole

We analyzed the influence of Trypanosoma cruzi maintenance in different hosts (dog and mouse) on its susceptibility to benznidazole treatment. Five T. cruzi stocks were isolated from dogs inoculated with Be-62 or Be-78 strain (both sensitive to benznidazole) 2-10 years ago, and the benznidazole sensitivity was then determined using the mouse as experimental model. The different T. cruzi stocks obtained from long-term infected dogs showed 50-90% drug resistance right after isolation. However, maintenance of these T. cruzi stocks in mice, by successive blood passages (2.5 years), led to either a decrease or stability of the drug resistance pattern and an increase in parasite virulence. We also demonstrated the effectiveness of the induction of parasitemia reactivation by cyclophosphamide immunosuppression in the evaluation of the response to the specific drug treatment.     

Trypanosoma cruzi: immunoglobulin isotype profiles during the acute phase of canine experimental infection with metacyclic or blood trypomastigotes

A detailed investigation has been carried out about the serological profiles of groups of dogs experimentally infected with metacyclic (MT) or blood (BT) trypomastigotes of Berenice-78 Trypanosoma cruzi strain. Peripheral blood was collected from infected dogs and uninfected controls, weekly during 35 days following the acute phase of infection, and immunoglobulin profiles were determined by ELISA. Dogs infected with BT exhibited unaltered levels of IgG2, increases in IgM, IgE, IgA, IgG and IgG1. In contrast, dogs infected with MT presented unaltered levels of IgE and IgG1 and an increase in IgM, IgA, IgG and IgG2 levels. Compared with the MT group, animals infected with BT showed significant increases in IgM on days 7, 14 and 28, in IgA on days 7, 14 and 21, in IgE on days 7 and 14, in IgG on days 14 and 28, and in IgG1 on days 7, 14 and 21. Parasitemia levels of the infected animals were measured over the same time period. No correlations were found between the immunoglobulin profiles and the parasitemia levels. The results demonstrated that the inoculum source (BT or MT) influence the immunoglobulin isotype profile that may drive distinct outcome of acute canine Chagas disease.     

Genotoxic effects of white fluorescent light on human lymphocytes in vitro

Sources of light beams such as white fluorescent light, are present in our daily life to meet the needs of life in the modern world. This study was conducted with the objective of determining the possible genotoxic, cytotoxic and aneugenic effects caused by this agent in different stages of the cell cycle (G0/early G1, S, and late G2), using different cytogenetic parameters (sister chromatid exchanges––SCE, chromosome aberrations––CA, and detection of aneugenic effects) in lymphocytes from temporary cultures of human peripheral blood. WFL showed a genotoxic effect in vitro, expressed by an increase in the frequency of SCE's, regardless of the cell cycle stage. However, no increase in the frequency of CAs was observed. In addition, disturbances in cell cycle kinetics and chromosomal segregation were also observed. Taken together, such data may contribute to a better understanding and a different management in the use of phototherapy for some pathological conditions.     

Genotoxic effects of white fluorescent light on human lymphocytes in vitro

Sources of light beams such as white fluorescent light, are present in our daily life to meet the needs of life in the modern world. This study was conducted with the objective of determining the possible genotoxic, cytotoxic and aneugenic effects caused by this agent in different stages of the cell cycle (G0/early G1, S, and late G2), using different cytogenetic parameters (sister chromatid exchanges--SCE, chromosome aberrations--CA, and detection of aneugenic effects) in lymphocytes from temporary cultures of human peripheral blood. WFL showed a genotoxic effect in vitro, expressed by an increase in the frequency of SCE's, regardless of the cell cycle stage. However, no increase in the frequency of CAs was observed. In addition, disturbances in cell cycle kinetics and chromosomal segregation were also observed. Taken together, such data may contribute to a better understanding and a different management in the use of phototherapy for some pathological conditions.