S-allylCysteine Ester/Caffeic Acid Amide Hybrids as Promising Antiprotozoal Candidates: Synthesis, Biological Evaluation and Molecular Modeling Studies

Abstract In order to overcome the challenges of discovering new antiprotozoal drugs, we synthesized a new class of hybrids based on S-allylCysteine Ester/Caffeic Acid Amide and evaluated four of them against Trypanosoma cruzi and Plasmodium falciparum. Hybrid 6 exhibited good activity on T. cruzi with an EC50 value of 5.45 µM, whereas hybrid 3 was active over P. falciparum with an EC50 of 18.08 µM. All hybrids displayed a good selectivity index on P. falciparum. Molecular docking computations indicated that several hybrids have good binding affinities towards the protozoa related enzymes (Cruzipain or Falcipain-2) when compared against current inhibitors. In silico studies showed that conjugates 1-3 and 6 fulfilled optimal ADME characteristics, suggesting them as safe alternatives for oral treatment of protozoal infections.

Antileishmanial activity of synthetic analogs of the naturally occurring quinolone alkaloid N-methyl-8-methoxyflindersin.

Leishmaniasis is a neglected, parasitic tropical disease caused by an intracellular protozoan from the genus Leishmania. Quinoline alkaloids, secondary metabolites found in plants from the Rutaceae family, have antiparasitic activity against Leishmania sp. N-methyl-8-methoxyflindersin (1), isolated from the leaves of Raputia heptaphylla and also known as 7-methoxy-2,2-dimethyl-2H,5H,6H-pyran[3,2-c]quinolin-5-one, shows antiparasitic activity against Leishmania promastigotes and amastigotes. This study used in silico tools to identify synthetic quinoline alkaloids having structure similar to that of compound 1 and then tested these quinoline alkaloids for their in vitro antiparasitic activity against Leishmania (Viannia) panamensis, in vivo therapeutic response in hamsters suffering from experimental cutaneous leishmaniasis (CL), and ex vivo immunomodulatory potential in healthy donors' human peripheral blood (monocyte)-derived macrophages (hMDMs). Compounds 1 (natural), 2 (synthetic), and 8 (synthetic) were effective against intracellular promastigotes (9.9, 3.4, and 1.6 µg/mL medial effective concentration [EC50], respectively) and amastigotes (5.07, 7.94, and 1.91 µg/mL EC50, respectively). Compound 1 increased nitric oxide production in infected hMDMs and triggered necrosis-related ultrastructural alterations in intracellular amastigotes, while compound 2 stimulated oxidative breakdown in hMDMs and caused ultrastructural alterations in the parasite 4 h posttreatment, and compound 8 failed to induce macrophage modulation but selectively induced apoptosis of infected hMDMs and alterations in the intracellular parasite ultrastructure. In addition, synthetic compounds 2 and 8 improved the health of hamsters suffering from experimental CL, without evidence of treatment-associated adverse toxic effects. Therefore, synthetic compounds 2 and 8 are potential therapeutic candidates for topical treatment of CL.

Successful treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate: A case series.

Cutaneous leishmaniasis (CL) is a high-morbidity, vector-borne disease endemic to Colombia. Unlike conventional systemic antileishmanial therapy, intralesional meglumine antimoniate administration has fewer adverse effects and can be as effective and safe. We describe 12 patients treated with intralesional meglumine antimoniate: seven with primary and five with recurrent lesions. The majority (11/12) met all cure criteria after 1-7 sessions of meglumine antimoniate administration (1-5 mL). Adverse effects comprised mainly of local pain and edema. Intralesional meglumine antimoniate administration could be an excellent alternative treatment for uncomplicated CL; however, controlled clinical trials are needed to test the efficacy and safety thereof.

Successful treatment of cutaneous leishmaniasis with intralesional meglumine antimoniate: A case series

Abstract Cutaneous leishmaniasis (CL) is a high-morbidity, vector-borne disease endemic to Colombia. Unlike conventional systemic antileishmanial therapy, intralesional meglumine antimoniate administration has fewer adverse effects and can be as effective and safe. We describe 12 patients treated with intralesional meglumine antimoniate: seven with primary and five with recurrent lesions. The majority (11/12) met all cure criteria after 1-7 sessions of meglumine antimoniate administration (1-5 mL). Adverse effects comprised mainly of local pain and edema. Intralesional meglumine antimoniate administration could be an excellent alternative treatment for uncomplicated CL; however, controlled clinical trials are needed to test the efficacy and safety thereof.

Phenotypic and Functional Profiles of Antigen-Specific CD4+ and CD8+ T Cells Associated With Infection Control in Patients With Cutaneous Leishmaniasis.

The host immunological response is a key factor determining the pathogenesis of cutaneous leishmaniasis. It is known that a Th1 cellular response is associated with infection control and that antigen-specific memory T cells are necessary for the development of a rapid and strong protective cellular response. The present manuscript reports the analysis of the functional and phenotypic profiles of antigen-specific CD4+ and CD8+ T cells from patients cured of cutaneous leishmaniasis (CL), patients with an active process of cutaneous leishmaniasis, asymptomatic individuals with a positive Montenegro test and healthy donors (HD). Peripheral blood mononuclear cells (PBMCs) from the patients exhibited a lymphoproliferative capacity after stimulation with total soluble protein from either Leishmania panamensis (SLpA) or Leishmania infantum (SLiA) or with a recombinant paraflagellar rod protein-1 (rPFR1). Higher frequencies of antigen-specific TNAIVE cells, mainly following stimulation with rPFR1, were observed in asymptomatic and cured patients than in patients with active cutaneous leishmaniasis, while T cells from patients with active cutaneous leishmaniasis showed a higher percentage of effector memory T cells (TEM for CD4+ T cells and TEMRA for CD8+ T cells). The amount of antigen-specific CD57+/CD8+ TEMRA cells in patients with active cutaneous leishmaniasis was higher than that in cured patients and asymptomatic subjects. Regarding functionality, a more robust multifunctional CD8+ T cell response was detected in cured patients than in those with active cutaneous leishmaniasis. Moreover, cured patients showed a significant increase in the frequency of cells expressing a Th1-type cytotoxic production profile (IFN-γ+/granzyme-B/+perforin+). Patients with an active leishmaniosis process had a significantly higher frequency of CD8+ T cells expressing the inhibitory CD160 and 2B4 receptors than did cured patients. The expression profile observed in cured patients could be indicative of an imbalance toward a CD8+ Th1 response, which could be associated with infection control; consequently, the determination of this profile could be a useful tool for facilitating the clinical follow-up of patients with cutaneous leishmaniasis. The results also suggest a possible exhaustion process of CD8+ T cells associated with the evolution of Leishmania infection.

The Akt-like kinase of Leishmania panamensis: As a new molecular target for drug discovery.

The Akt-like kinase of Leishmania spp. is a cytoplasmic orthologous protein of the serine/threonine kinase B-PKB/human-Akt group, which is involved in the cellular survival of these parasites. By the application of a computational strategy we obtained two specific inhibitors of the Akt-like protein of L. panamensis (UBMC1 and UBMC4), which are predicted to bind specifically to the pleckstrin domain (PH) of the enzyme. We show that the Akt-like of Leishmania panamensis is phospho-activated in parasites under nutritional and thermic stress, this phosphorylation is blocked by the UBMC1 and UMBC2 and such inhibition leads to cell death. Amongst the effects caused by the inhibitors on the parasites we found high percentage of hypodiploidy and loss of mitochondrial membrane potential. Ultrastructural studies showed highly vacuolated cytoplasm, as well as shortening of the flagellum, loss of nuclear membrane integrity and DNA fragmentation. Altogether the presented results suggest that the cell death caused by UMBC1 and UMBC4 may be associated to an apoptosis-like process. The compounds present an inhibitory concentration (IC50) over intracellular amastigotes of L. panamensis of 9.2±0.8µM for UBMC1 and 4.6±1.9µM for UBMC4. The cytotoxic activity for UBMC1 and UBMC4 in human macrophages derived from monocytes (huMDM) was 29±1.2µM and >40µM respectively. Our findings strongly support that the presented compounds can be plausible candidates as a new therapeutic alternative for the inhibition of specific kinases of the parasite.

In vitro and in vivo antileishmanial activity of Artemisia annua L. leaf powder and its potential usefulness in the treatment of uncomplicated cutaneous leishmaniasis in humans.

INTRODUCTION:: Cutaneous leishmaniasis (CL) is a tropical disease that affects millions of individuals worldwide. The current drugs for CL may be effective but have serious side effects; hence, alternatives are urgently needed. Although plant-derived materials are used for the treatment of various diseases in 80% of the global population, the validation of these products is essential. Gelatin capsules containing dried Artemisia annua leaf powder were recently developed as a new herbal formulation (totum) for the oral treatment of malaria and other parasitic diseases. Here, we aimed to determine the usefulness of A. annua gel capsules in CL. METHODS:: The antileishmanial activity and cytotoxicity of A. annua L. capsules was determined via in vitro and in vivo studies. Moreover, a preliminary evaluation of its therapeutic potential as antileishmanial treatment in humans was conducted in 2 patients with uncomplicated CL. RESULTS:: Artemisia annua capsules showed moderate in vitro activity in amastigotes of Leishmania (Viannia) panamensis; no cytotoxicity in U-937 macrophages or genotoxicity in human lymphocytes was observed. Five of 6 (83.3%) hamsters treated with A. annua capsules (500mg/kg/day) for 30 days were cured, and the 2 examined patients were cured 45 days after initiation of treatment with 30g of A. annua capsules, without any adverse reactions. Both patients remained disease-free 26 and 24 months after treatment completion. CONCLUSION:: Capsules of A. annua L. represent an effective treatment for uncomplicated CL, although further randomized controlled trials are needed to validate its efficacy and safety.

In vitro and in vivo antileishmanial activity of Artemisia annua L. leaf powder and its potential usefulness in the treatment of uncomplicated cutaneous leishmaniasis in humans

ABSTRACT INTRODUCTION: Cutaneous leishmaniasis (CL) is a tropical disease that affects millions of individuals worldwide. The current drugs for CL may be effective but have serious side effects; hence, alternatives are urgently needed. Although plant-derived materials are used for the treatment of various diseases in 80% of the global population, the validation of these products is essential. Gelatin capsules containing dried Artemisia annua leaf powder were recently developed as a new herbal formulation (totum) for the oral treatment of malaria and other parasitic diseases. Here, we aimed to determine the usefulness of A. annua gel capsules in CL. METHODS: The antileishmanial activity and cytotoxicity of A. annua L. capsules was determined via in vitro and in vivo studies. Moreover, a preliminary evaluation of its therapeutic potential as antileishmanial treatment in humans was conducted in 2 patients with uncomplicated CL. RESULTS: Artemisia annua capsules showed moderate in vitro activity in amastigotes of Leishmania (Viannia) panamensis; no cytotoxicity in U-937 macrophages or genotoxicity in human lymphocytes was observed. Five of 6 (83.3%) hamsters treated with A. annua capsules (500mg/kg/day) for 30 days were cured, and the 2 examined patients were cured 45 days after initiation of treatment with 30g of A. annua capsules, without any adverse reactions. Both patients remained disease-free 26 and 24 months after treatment completion. CONCLUSION: Capsules of A. annua L. represent an effective treatment for uncomplicated CL, although further randomized controlled trials are needed to validate its efficacy and safety.

[Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities]. / Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica.

INTRODUCTION: Leishmaniasis is a major public health problem faced by many countries, including Colombia. Its treatment has limitations such as the toxicity of the drugs used, the emergence of resistant strains, and prolonged and expensive treatments. Thus, there is an urgent need to find alternative solutions. OBJECTIVE: To evaluate the leishmanicidal and cytotoxic activities of three 2-styrylquinolines type compounds: 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl]quinolin-8-yl-acetate, E1; 2-[(E)-2-(4-acetyloxy-3-methoxyphenyl)ethenyl] quinoline, E2, and 2-[(E)-2-(2,3-diacetyloxyphenyl)ethenyl] quinoline, E3. MATERIALS AND METHODS: The 2-styrylquinolines were obtained by organic synthesis using Perkin-type condensation reaction from 8-hydroxy quinaldine or quinaldine and aromatic aldehydes. The leishmanicidal activity was evaluated on intracellular amastigotes of Leishmania (Viannia) panamensis by flow cytometry. The results were expressed as lethal concentration 50 (LC 50 ) for cytotoxicity and effective concentration 50 (EC 50 ) for leishmanicidal activity, calculated by the Probit method. RESULTS: E3 showed high activity against L. (V) panamensis with a calculated EC 50 value of 1.4 µg/ml, and a selectivity index of 3.9; E1 and E2 showed higher EC 50 values of 5.6 and 68.1 µg/ml, respectively. For cytotoxicity, LC 50 values ranging from 5.4 to 68.1 µg/ml were calculated. E2 was moderately toxic, showing an LC 50 very similar to that of amphotericin B, a substance used as cytotoxic control. CONCLUSION: The styrylquinoline E3 is a promising compound against L. (V) panamensis , as it was able to significantly inhibit amastigotes inside the cell, reducing infection despite its toxicity.

Compuestos sintéticos del tipo de estirilquinolinas con actividades leishmanicida y citotóxica / Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities

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Actividad tripanocida y citotóxica de extractos de plantas colombianas / Trypanocidal and cytotoxic activity of extracts of Colombian plants

Introducción. El tratamiento de la enfermedad de Chagas está basado en sólo dos medicamentos de eficacia limitada y con importantes efectos colaterales. La gran biodiversidad de la flora colombiana hace de la bioprospección una alternativa potencial en la búsqueda de nuevos antiparasitarios. Objetivo. Evaluar in vitro el potencial tripanocida y la citotoxicidad de extractos obtenidos de 23 plantas colombianas. Materiales y métodos. Se obtuvieron extractos de hojas, de tallos o de la planta entera, en solventes de diferente polaridad. La actividad contra epimastigotes y la citotoxicidad se evaluaron por el micrométodo enzimático con MTT. Los extractos activos contra epimastigotes y con baja citotoxicidad se evaluaron también en tripomastigotes y amastigotes intracelulares. Resultados. Se reporta la actividad tripanocida de 13 plantas colombianas y se confirma el efecto biológico de cuatro especies previamente evaluadas. Cuatro extractos activos en epimastigotes también fueron activos en tripomastigotes y, uno de ellos, en amastigotes. Este extracto fue aislado de la planta Hieronyma antioquensis, y presentó CI50 de 3,125, 11,48 y 2,85 µg/ml, e índices de selectividad de 25,7 y 27, para epimastigotes, tripomastigotes y amastigotes, respectivamente. Los resultados sugieren que este extracto es un candidato promisorio para el tratamiento de la enfermedad de Chagas. Conclusión. La flora colombiana es una fuente potencial de nuevas sustancias para la quimioterapia contra la enfermedad de Chagas. El micrométodo enzimático con MTT es una herramienta útil para la tamización de la actividad biológica en epimastigotes y posterior selección para ensayos con otros estadios del parásito.

Introduction. The treatment of Chagas disease is based on only two drugs with limited efficacy and significant side effects. The rich biodiversity of the Colombian flora makes bio-prospecting a potential alternative in the search for new antiparasitic drugs. Objective. Potential trypanocidal activity and cytotoxicity was assessed in extracts from 23 Colombian plants. Materials and methods. Extracts of leaves, stems, or of the whole plants were obtained in solvents of a range of polarities. The activity against Trypanosoma cruzi epimastigotes and the cytotoxicity were evaluated by the MTT enzymatic micro-method. Extracts active against epimastigotes and with lowcytotoxicity were also tested on trypomastigotes and intracellular amastigotes. Results. Among the extracts, biological activity was confirmed in 4 species. The extracts were active on epimastigotes and trypomastigotes; one was active also against amastigotes. The latter extract was isolated from the plant Hieronyma antioquensis and presented IC50 of 3.1 mg/ml for epimastigotes, 11.5mg/ml for trypomastigotes and 2.9 mg/ml for amastigotes. The selectivity indexes were 25, 7, and 27 respectively. Conclusions. The extract from H. antioquensis proved a promising candidate for Chagas disease treatment. Futhermore, the MTT enzymatic micromethod was a useful tool for screening biological activity on epimastigotes and other stages of the parasite for further extract trials.

Leishmania (Viannia) panamensis expresses a nuclease with molecular and biochemical features similar to the Endonuclease G of higher eukaryotes / Leishmania (Viannia) panamensis expresa una nucleasa molecular y bioquímicamente similar a la Endonucleasa G de eucariotas superiores

Objective: To characterize the molecular and biochemical features of the Endonuclease G of Leishmania (Viannia) panamensis.Methods: The gene of the putative L. (V.) panamensis Endonuclease G was amplified, cloned, and sequenced. The recombinant protein was produced in a heterologous expression system and biochemical assays were run to determine its ion, temperature, and pH preferences.Results: The L. (V.) panamensis rENDOG has biochemical features similar to those found in other trypanosomatids and higher eukaryotes. In addition, phylogenetic analysis revealed a possible evolutionary relationship with metazoan ENDOG.Conclusions: L. (V.) panamensis has a gene that codifies an ENDOG homologous to those of higher organisms. This enzyme can be produced in Escherichia coli and is able to degrade covalently closed circular double-stranded DNA. It has a magnesium preference, can be inhibited by potassium, and is able to function within a wide temperature and pH range.

Objetivo: Caracterizar molecular y bioquímicamente la Endonucleasa G (EndoG) de Leishmania (Viannia) panamensis.Métodos: El gen de la putativa Endonucleasa G de L. (V.) panamensis fue amplificado, clonado y secuenciado. La proteína recombinante se produjo en un sistema de expresión heterólogo y la proteína activa se sometió a pruebas bioquímicas para determinar la preferencia de iones, temperatura y pH.Resultados: La rEndoG de L. (V.) panamensis muestra características bioquímicas similares a aquellas descritas en otros trypanosomatidos y en eucariotas superiores. Además, los análisis filogenéticos muestran una posible relación evolutiva con la Endonucleasa G de metazoos.Conclusiones: Leishmania (V.) panamensis posee un gen que codifica para una endonucleasa homóloga a la EndoG de otros organismos superiores, que se puede producir de forma recombinante en Escherichia coli y que es capaz de degradar ADN circular cerrado de doble cadena. Tiene una preferencia por los iones magnesio y manganeso para usarlos como cofactor y es inhibida por el potasio. Además, funciona en un amplio rango de pH y temperatura.

[Trypanocidal and cytotoxic activity of extracts of Colombian plants]. / Actividad tripanocida y citotóxica de extractos de plantas colombianas.

INTRODUCTION: The treatment of Chagas disease is based on only two drugs with limited efficacy and significant side effects. The rich biodiversity of the Colombian flora makes bio-prospecting a potential alternative in the search for new antiparasitic drugs. OBJECTIVE: Potential trypanocidal activity and cytotoxicity was assessed in extracts from 23 Colombian plants. MATERIALS AND METHODS: Extracts of leaves, stems, or of the whole plants were obtained in solvents of a range of polarities. The activity against Trypanosoma cruzi epimastigotes and the cytotoxicity were evaluated by the MTT enzymatic micro-method. Extracts active against epimastigotes and with low cytotoxicity were also tested on trypomastigotes and intracellular amastigotes. RESULTS: Among the extracts, biological activity was confirmed in 4 species. The extracts were active on epimastigotes and trypomastigotes; one was active also against amastigotes. The latter extract was isolated from the plant Hieronyma antioquensis and presented IC(50) of 3.1 mg/ml for epimastigotes, 11.5 mg/ml for trypomastigotes and 2.9 mg/ml for amastigotes. The selectivity indexes were 25, 7, and 27 respectively. CONCLUSIONS: The extract from H. antioquensis proved a promising candidate for Chagas disease treatment. Futhermore, the MTT enzymatic micromethod was a useful tool for screening biological activity on epimastigotes and other stages of the parasite for further extract trials.

Presencia de infestación por Fasciola hepatica en habitantes del valle de San Nicolás, oriente antioqueño / Presence of infection by Fasciola hepatica in inhabitants from the valle de San Nicolás, eastern Antioquia

Introducción. En estudios previos se han encontrado prevalencias hasta de 90% de fasciolosis hepática en el ganado bovino del valle de San Nicolás en el oriente antioqueño. Objetivo. En este estudio se determinó la presencia de infestación en la población humana que está en contacto con el ganado de la región. Materiales y métodos. La presencia de anticuerpos en muestras de suero de 61 personas residentes de la zona y cuyos trabajos exigían contacto constante con ganado bovino, se determinó mediante una prueba tipo ELISA específica para Fasciola. hepatica. También se determinaron las conductas de riesgo para la adquisición del parásito, al igual que los antecedentes clínicos para la población estudiada. Resultados. Tres de los 61 sueros fueron positivos para la presencia de anticuerpos específicos para F. hepatica que corresponde a una prevalencia de infestación de 4,9%. Los tres individuos con muestras positivas relataron manipular pastos para ganadería y beber agua de las quebradas aledañas a las zonas de pastoreo. Sólo una de las personas con suero positivo refirió haber presentado ictericia en los últimos seis meses. Conclusiones Los resultados documentan la presencia de F. hepatica en la población humana que se encuentra en contacto con ganado infectado y permiten identificar las conductas de riesgo para la adquisición de la enfermedad en los habitantes de la zona. Es importante conocer la incidencia y prevalencia de la infestación, tanto en la población humana como animal, para adoptar medidas de prevención de las personas que están en contacto con el ganado enfermo, así como para tratar las personas enfermas.

Introduction: The Programa de Estudio y Control de Enfermedades Tropicales (PECET) at the Universidad de Antioquia has found a prevalence of 90% of hepatic fasciolasis in cattle from valle de San Nicolás, eastern Antioquia. Objective: In this study the presence of infection in the human population that is in contact with livestock was determined. Materials and methods: The presence of antibodies in serum samples from 61 residents of the area and whose jobs require constant contact with cattle was determined by an ELISA test. Risk behaviors for acquisition of the parasite as well as the clinical and symptoms for the study population were also determined.Results: Three of the 61 sera tested were positive for the presence of specific antibodies to F. hepatica, corresponding to a prevalence of infection of 4.9%. These three subjects reported manipulating pasture for livestock and drinking water from streams near grazing fields. Only one person referred jaundice in the last six months. Conclusions: The findings of this study document the presence of F. hepatica in the human population that is in contact with infected livestock and identify the risk behaviors for acquisition of the disease among the inhabitants of the area. It is important to know the incidence and prevalence of infection in both human and animal population, to adopt preventive measures for those that are in contact with sick cattle, and treatment of infected people.

[Efficacy and tolerance of pentamidine for treatment of cutaneous leishmaniasis caused by por L. (V) panamensis in Colombia]. / Eficacia y tolerancia de la pentamidina en el tratamiento de la leishmaniasis cutánea producida por Leishmania (V.) panamensis en Colombia.

INTRODUCTION: Current treatment for human cutaneous leishmaniasis (CL) relies on pentavalent antimonials. Although efficacy of these drugs is high (around 85%), their widely documented toxicity and increasing resistance makes the search for therapeutic alternatives a priority for endemic countries. OBJECTIVE: To evaluate the efficacy and tolerability of the pentamidine isethionate for the treatment of cutaneous leishmaniasis caused by L. (V) panamensis in a pilot clinical trial. MATERIALS AND METHODS: Sixty three individuals suffering CL were enrolled. Patients received four intramuscular injections of pentamidine (4 mg/Kg/injection) administered every other day, and both clinical efficacy and side effects were documented during the following 6 months. RESULTS: Of the 63 patients enrolled, 43 could be followed for 6 months. 86% (37/43) of treated patients healed all their lesions by 1.5 months after therapy. Treatment failure was observed in only five patients (11.6%; 5/43). One patient showed relapse. Overall tolerance of treatment was good, with adverse events such as local pain and swelling at the site of injection, dizziness and fever, varying from mild to moderate. Hypoglycemia, hypotension or diabetes were not observed. DISCUSSION: These results confirm the previously reported efficacy of pentamidine for the treatment of CL in Colombia and Brazil, and, additionally, highlight the low intensity and frequency of side effects in a civilian population. No serious adverse events were recorded.

[Role of Langerhans cells in the immunity of leishmaniasis]. / Las células de Langerhans en la inmunidad a leishmaniasis.

Immune response induced against Leishmania parasites is influenced by several factors, one of the most important being the type of Antigen Presenting Cell (APC). Langerhans cells, a subpopulation of APC, are sentinel cells for detecting invader microorganisms; they reside in skin tissues at levels where the phlebotomine fly vector inoculates Leishmania parasites. Presence of microorganisms can induce activation of Langerhans cells, leading to their maturation and migration towards lymph nodes. There, Langerhans cells present antigens to T cells for their subsequent activation and specific differentiation into effector cells. Early after a Leishmania infection, few T cells have been observed at sites of infection, suggesting that infected macrophages have little opportunity to locate T cells specific for elimination of Leishmania parasites. However, Langerhans cells may be the cells available to provide signals for the stimulation of parasite-specific T-cell responses in the lymph node and for inducing T-cell migration to the infected skin. Herein, the main characteristics of Langerhans cells are reviewed, with special emphasis on their participation in cutaneous inflammatory response. The role of these cells in infections caused by protozoan parasites of the Leishmania genus is discussed.

Las células de Langerhans en la inmunidad a leishmaniasis / Role of Langerhans cells in the immunity of leishmaniasis

En la respuesta inmune a parásitos del género Leishmania influyen múltiples factores entre los que se encuentran no sólo los relacionados con el parásito sino también aquéllos relacionados con el hospedero; de particular importancia es el tipo participante de célula presentadora de antígenos. En la piel, lugar donde el vector inocula el parásito, se encuentran las células de Langerhans que tienen como principal función servir como centinelas para la detección de microorganismos invasores. El estímulo que genera el microorganismo o las células circundantes induce la activación de las células de Langerhans, su maduración y migración hacia el tejido linfoide local (regional) donde presentan los antígenos a las células T para la posterior activación y diferenciación de subpoblaciones de células T específicas, responsables de la resolución de la infección o de la cicatrización. Se ha observado que durante la fase temprana de la infección con Leishmania hay muy pocas células T en el sitio de la infección lo cual sugiere que los macrófagos infectados tienen pocas probabilidades de encontrar allí células T con la especificidad requerida para eliminar el parásito y que, por tanto, son las células de Langerhans las que proporcionan la señal que activa las células T específicas para Leishmania en los ganglios linfáticos locales que drenan de la lesión e inducen su migración al sitio de la lesión. En la presente revisión se abordan las principales características de las células de Langerhans, se hace especial énfasis en la participación en la respuesta inflamatoria cutánea y se presentan los hallazgos más relevantes del papel de estas células en el modelo de infección por parásitos del género Leishmania

Leishmaniosis cutánea en Colombia y género / Gender and cutaneous leishmaniasis in Colombia

Em Colômbia, tradicionalmente se ha visto la leishmaniosis como un problema de Salud Pública para hombres adultos dado que se considera que la transmisión es selvática y que ellos empiezan a infectarse cuando entran a los biotopos del vector con el fin de utilizar los recursos naturales. Sin embargo, el Programa de Estudio y Control de Enfermedades Tropicales (PECET) ha observado iguales proporciones de hombres y mujeres con leishmaniosis activa y pruebas cutáneas positivas. Alguns factores, hasta ahora nunca analizados, parecen distorsionar el patrón de la enfermedad y al parecer existen diferencias inherentes al género relacionadas con el acceso a la atención en salud. Como consecuencia, el sufrimiento humano no es aliviado y las repercusiones socio-económicas para las amas de casa son significativas. El Ministerio de Salud subestima la magnitud de la transmisión intra y peridomiciliaria y la detección de casos activos se descuida para mujeres, por lo cual se deben mejorar los programas de control de leishmaniosis, especialmente en lo relacionado con la detección de casos activos, entrenamiento y educación, de tal forma que el diagnóstico se realice en forma más rápida.

Receptores Fc. Distribución, estructura y función

Muchas de las funciones esenciales del sistema inmune son mediadas por glicoproteínas de superficie conocidas como receptores Fc (FcR), que interaccionan en forma específica con el dominio constante o región Fc de inmunoglobulinas homólogas. Se encuentran ampliamente distribuidos entre las células del sistema inmune y tienen especificidad por diferentes isotipos de inmunoglobulinas. Las cadenas proteicas que componen los FcR contienen una región extracelular, una región transmembranal y una región intracelular. La región extracelular es altamente conservada mientras que la citoplasmática es muy heterogénea, lo que parece explicar las diferencias funcionales existentes entre los FcR expresados por las distintas células. El análisis molecular de genes y proteínas que constituyen los FcR ha mostrado una diversidad de estructuras, subunidades proteicas y vías para la transducción de señales que son compartidas con otros receptores del sistema inmune. Conocer las funciones específicas para cada uno de los FcR y el mecanismo a través del cual ocurre la transducción de señales para la activación celular permitirá un mejor entendimiento del papel inmunorregulador de los FcR y su utilización en el diseño de alternativas terapéuticas para varios desórdenes inmunológicos en los cuales participan.