Carlos Eduardo Sampaio Guedes

Universidade Federal da Bahia

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Patrícia Sampaio Tavares Veras

Fundação Oswaldo Cruz

Manuela da Silva Solcà

Universidade Federal da Bahia

Antônio Luis de Oliveira Almeida Petersen

Fundação Oswaldo Cruz

Deborah Bittencourt Mothé Fraga

Fundação Oswaldo Cruz

Juliana Perrone Bezerra de Menezes

Fundação Oswaldo Cruz

José Geraldo Bomfim Lima

Fundação Oswaldo Cruz

Eliane Gomes Nascimento

Geraldo Gileno de Sá Oliveira

Fundação Oswaldo Cruz

Valéria M. Borges

Fundação Oswaldo Cruz

Washington L. C. dos‐Santos

Fundação Oswaldo Cruz

Cooperative Institutions

Fundação Oswaldo Cruz

Universidade Federal da Bahia

Hospital Ana Nery

Universidade Federal de Minas Gerais

Complexo Hospitalar Universitário Professor Edgard Santos

Universidade de São Paulo

Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais

Universidade do Estado da Bahia

Universidade Federal do Pará

Fundação Carlos Chagas

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Advances in Development of New Treatment for Leishmaniasis

BioMed Research International (2015)

Juliana Perrone Bezerra de Menezes Carlos Eduardo Sampaio Guedes Antônio Luis de Oliveira Almeida Petersen Deborah Bittencourt Mothé Fraga Patrícia Sampaio Tavares Veras

Leishmaniasis is a neglected infectious disease caused by several different species of protozoan parasites of the genus Leishmania . Current strategies to control this disease are mainly based on chemotherapy. Despite being available for the last 70 years, leishmanial chemotherapy has lack of efficiency, since its route of administration is difficult and it can cause serious side effects, which results in the emergence of resistant cases. The medical-scientific community is facing difficulties to overcome these problems with new suitable and efficient drugs, as well as the identification of new drug targets. The availability of the complete genome sequence of Leishmania has given the scientific community the possibility of large-scale analysis, which may lead to better understanding of parasite biology and consequent identification of novel drug targets. In this review we focus on how high-throughput analysis is helping us and other groups to identify novel targets for chemotherapeutic interventions. We further discuss recent data produced by our group regarding the use of the high-throughput techniques and how this helped us to identify and assess the potential of new identified targets.

Identification

10.1155/2015/815023

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Citations (189)

17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages

PLoS ONE (2012)

Antônio Luis de Oliveira Almeida Petersen Carlos Eduardo Sampaio Guedes Carolina Leite Versoza José Geraldo Bomfim Lima Luiz Antônio Rodrigues de Freitas

Background Leishmaniasis is a neglected endemic disease with a broad spectrum of clinical manifestations. Pentavalent antimonials have been the treatment of choice for the past 70 years and, due to the emergence of resistant cases, the efficacy of these drugs has come under scrutiny. Second-line drugs are less efficacious, cause a range of side effects and can be costly. The formulation of new generations of drugs, especially in developing countries, has become mandatory. Methodology/Principal Findings We investigated the anti-leishmanial effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, in vitro. This inhibitor is currently in clinical trials for cancer treatment; however, its effects against intracellular Leishmania remain untested. Macrophages infected with L. amazonensis were treated with 17-AAG (25–500 nM) and parasite load was quantified using optical microscopy. Parasite load declined in 17-AAG-treated macrophages in a dose- and time-dependent manner. Intracellular parasite death became irreversible after 4 h of treatment with 17-AAG, and occurred independent of nitric oxide (NO) and superoxide (O2−) production. Additionally, intracellular parasite viability was severely reduced after 48 h of treatment. Interestingly, treatment with 17-AAG reduced pro-inflammatory mediator production, including TNF-α, IL-6 and MCP-1, yet IL-12 remained unaffected. Electron microscopy revealed morphological alterations, such as double-membrane vacuoles and myelin figures at 24 and 48 h after 17-AAG treatment. Conclusions/Significance The HSP90 inhibitor, 17-AAG, possesses high potency under low dosage and reduces both pro-inflammatory and oxidative molecule production. Therefore, further studies are warranted to investigate this inhibitor's potential in the development of new generations of anti-leishmanials.

Intracellular parasite

Hsp90 inhibitor

Leishmania mexicana

Parasite load

10.1371/journal.pone.0049496

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Citations (44)

Proteomic analysis reveals differentially expressed proteins in macrophages infected with Leishmania amazonensis or Leishmania major

Microbes and Infection (2013)

Juliana Perrone Bezerra de Menezes Taís Fontoura de Almeida Antonio L. O. A. Petersen Carlos Eduardo Sampaio Guedes Manoel Santos Mota

CBA macrophages effectively control Leishmania major infection, yet are permissive to Leishmania amazonensis. Employing a transcriptomic approach, we previously showed the up-regulation of the genes involved in the classical pathway of macrophage activation in resistant mice. However, microarray analyses do not evaluate changes in gene expression that occur after translation. To circumvent this analytical limitation, we employed a proteomics approach to increase our understanding of the modulations that occur during infection and identify novel targets for the control of Leishmania infection. To identify proteins whose expression changes in CBA macrophages infected with L. major or L. amazonensis, protein extracts were obtained and digested and the peptides were characterized using multi-dimensional liquid chromatography coupled with tandem mass spectrometry analyses. A total of 162 proteins were selected as potentially modulated. Using biological network analyses, these proteins were classified as primarily involved in cellular metabolism and grouped into cellular development biological networks. This study is the first to use a proteomics approach to describe the protein modulations involved in cellular metabolism during the initial events of Leishmania-macrophage interaction. Based on these findings, we hypothesize that these differentially expressed proteins likely play a pivotal role in determining the course of infection.

Tandem mass tag

Kinetoplastida

Proteome

Biological pathway

10.1016/j.micinf.2013.04.005

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Citations (40)

Evaluating the Accuracy of Molecular Diagnostic Testing for Canine Visceral Leishmaniasis Using Latent Class Analysis

PLoS ONE (2014)

Manuela da Silva Solcà Leila Andrade Bastos Carlos Eduardo Sampaio Guedes Marcelo Bordoni Lairton Souza Borja

Host tissues affected by Leishmania infantum have differing degrees of parasitism. Previously, the use of different biological tissues to detect L. infantum DNA in dogs has provided variable results. The present study was conducted to evaluate the accuracy of molecular diagnostic testing (qPCR) in dogs from an endemic area for canine visceral leishmaniasis (CVL) by determining which tissue type provided the highest rate of parasite DNA detection. Fifty-one symptomatic dogs were tested for CVL using serological, parasitological and molecular methods. Latent class analysis (LCA) was performed for accuracy evaluation of these methods. qPCR detected parasite DNA in 100% of these animals from at least one of the following tissues: splenic and bone marrow aspirates, lymph node and skin fragments, blood and conjunctival swabs. Using latent variable as gold standard, the qPCR achieved a sensitivity of 95.8% (CI 90.4–100) in splenic aspirate; 79.2% (CI 68–90.3) in lymph nodes; 77.3% (CI 64.5–90.1) in skin; 75% (CI 63.1–86.9) in blood; 50% (CI 30–70) in bone marrow; 37.5% (CI 24.2–50.8) in left-eye; and 29.2% (CI 16.7–41.6) in right-eye conjunctival swabs. The accuracy of qPCR using splenic aspirates was further evaluated in a random larger sample (n = 800), collected from dogs during a prevalence study. The specificity achieved by qPCR was 76.7% (CI 73.7–79.6) for splenic aspirates obtained from the greater sample. The sensitivity accomplished by this technique was 95% (CI 93.5–96.5) that was higher than those obtained for the other diagnostic tests and was similar to that observed in the smaller sampling study. This confirms that the splenic aspirate is the most effective type of tissue for detecting L. infantum infection. Additionally, we demonstrated that LCA could be used to generate a suitable gold standard for comparative CVL testing.

Gold standard (test)

10.1371/journal.pone.0103635

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Citations (47)

Qualitative and quantitative polymerase chain reaction (PCR) for detection of Leishmania in spleen samples from naturally infected dogs

Veterinary Parasitology (2011)

Manuela da Silva Solcà Carlos Eduardo Sampaio Guedes Eliane Gomes Nascimento Geraldo Gileno de Sá Oliveira W. Santos

Kinetoplast

Minicircle

Leishmania chagasi

Canine leishmaniasis

10.1016/j.vetpar.2011.08.026

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Citations (42)

Enzyme activity of cellulases produced by Moniliophtora perniciosa, the causing factor of “witch–broom” in cacao plants

Magistra Media Pengembangan Ilmu Pendidikan Dasar dan Keislaman (2017)

Carlos Eduardo Sampaio Guedes Rita C. Alvarez Eduardo Aquino Ximenes Luis Cesar Maffei Sartini Paulillo Suzana Telles da Cunha Lima

Abstract : Cellulases are applied in food and textile industry, in the production of alcoholic beverages, bioconversion of agronomic residues and, increasingly, for production of biofuels. The fungi of cacao plants are very resistant and difficult to combat. On the other hand, enzymes produced by them have numerous biotechnological applications. The present work aimed to evaluate isolates of Moniliophtora perniciosa representatives from the Reconcavo region of Bahia, in Brazil, regarding the production of cellulases. Thirty two M. perniciosa strains were evaluated while growing in the presence of cellulose as the only carbon source. They were initially screened using the Congo red assay, following halo formation, after growth in solid medium containing one of the substrates mentioned before. Of the tested strains, 948F showed the greatest potential for the hydrolysis of non-crystalline cellulose. This strain was further tested for its ability to produce cellulases in minimal liquid medium in the presence of carboximetil cellulose (CMC) as the only carbon source. The maximal growth range was between 168 and 192 h. The highest activity values were observed between 240 and 246 h, maximum value being 10.5 U/mL x 10 -3 . The zymogram analysis showed the presence of three bands with endoglucanase activity. Although the results obtained are preliminary, they may open the way for future investigations of this strain aiming optimization of conditions for production of cellulases and other hydrolytic enzymes with potential biotechnological applications. Key words : Theobroma cacao , Endoglucanases, Hydrolytic enzymes.

Bioconversion

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Citations (18)

Encapsulation of Living Leishmania Promastigotes in Artificial Lipid Vacuoles

PLoS ONE (2015)

Carlos Eduardo Sampaio Guedes José Geraldo Bomfim Lima Emmanuèle Helfer Patrícia Sampaio Tavares Veras Annie Viallat

After phagocytosis by mammalian macrophages, promastigote forms of Leishmania parasites settle inside intracellular parasitophorous vacuoles (PVs) in which they transform into amastigote forms and replicate. Here, using a variant of the ‘inverted emulsion’ method, we succeeded in encapsulating living L. amazonensis parasites in giant artificial liposomes that serve as model PVs. We were able to control the size of liposomes, the pH and the composition of their internal volume, and the number of internalized parasites per liposome. L. amazonensis promastigotes encapsulated in liposomes filled with RPMI-Dextran solution at pH 7.5 or 6.5 survived up to 96 h at 24°C. At 37°C and pH 5.5, parasites survived 48h. This method paves the way to identifying certain effectors secreted by the parasite and to unraveling specific mechanisms of fusion between the PV and intracellular vesicles of the host cell. This method will also facilitate the study of the temporal evolution of biophysical properties of the PV during its maturation.

Amastigote

Leishmania mexicana

Intracellular parasite

10.1371/journal.pone.0134925

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Citations (5)

An Assessment of the Genetic Diversity of Leishmania infantum Isolates from Infected Dogs in Brazil

American Journal of Tropical Medicine and Hygiene (2012)

Luís Fábio da Silva Batista Marcela Segatto Carlos Eduardo Sampaio Guedes Rosana S. Sousa Cleusa Alves Theodoro Rodrigues

Correlations between the genetic diversity of Leishmania infantum (syn. L. chagasi) isolates and their respective geographic origins support the theoretic assumption that visceral leishmaniasis probably originated in the Old World. Because dogs are widely considered to be the main reservoir of this disease, the present study aimed to investigate the degree of genetic divergence among 44 leishmanial canine isolates from two Brazilian cities, Jequié and Campo Grande, located approximately 2,028 km from each other. We hypothesized that a low degree of genetic divergence would be observed among these isolates. In fact, statistical analyses found no significant differences between the isolates using both random amplified polymorphic DNA and multilocus microsatellite typing genotyping techniques with three and seven markers, respectively. These findings provide support for the recent introduction of L. infantum into the New World.

Genetic divergence

Multilocus sequence typing

10.4269/ajtmh.2012.11-0300

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Citations (14)

Proteomic analysis as a tool identify macrophage targets for anti-Leishmania chemotherapy

Juliana Perrone Bezerra de Menezes Taís Fontoura de Almeida Antônio Luis de Oliveira Almeida Petersen Carlos Eduardo Sampaio Guedes Manoel Santos Mota

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Citations (0)

Using molecular detection and qualification methods to diagnose canine visceral leishmaniasis

Manuela da Silva Solcà Leila Andrade Bastos Carlos Eduardo Sampaio Guedes Marcelo Bordoni Gonçalves Eliane Gomes Nascimento