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1.
Prog Chem Org Nat Prod ; 115: 115-176, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33797642

RESUMEN

Secondary metabolites (SM) from organisms have served medicinal chemists over the past two centuries as an almost inexhaustible pool of new drugs, drug-like skeletons, and chemical probes that have been used in the "hunt" for new biologically active molecules with a "beneficial effect on human mind and body." Several secondary metabolites, or their derivatives, have been found to be the answer in the quest to search for new approaches to treat or even eradicate many types of diseases that oppress humanity. A special place among SM is occupied by lignans and neolignans. These phenolic compounds are generated biosynthetically via radical coupling of two phenylpropanoid monomers, and are known for their multitarget activity and low toxicity. The disadvantage of the relatively low specificity of phenylpropanoid-based SM turns into an advantage when structural modifications of these skeletons are made. Indeed, phenylpropanoid-based SM previously have proven to offer great potential as a starting point in drug development. Compounds such as Warfarin® (a coumarin-based anticoagulant) as well as etoposide and teniposide (podophyllotoxin-based anticancer drugs) are just a few examples. At the beginning of the third decade of the twenty-first century, the call for the treatment of more than a dozen rare or previously "neglected" diseases remains for various reasons unanswered. Leishmaniasis, a neglected disease that desperately needs new ways of treatment, is just one of these. This disease is caused by more than 20 leishmanial parasites that are pathogenic to humans and are spread by as many as 800 sandfly species across subtropical areas of the world. With continuing climate changes, the presence of Leishmania parasites and therefore leishmaniasis, the disease caused by these parasites, is spreading from previous locations to new areas. Thus, leishmaniasis is affecting each year a larger proportion of the world's population. The choice of appropriate leishmaniasis treatment depends on the severity of the disease and its form of manifestation. The success of current drug therapy is often limited, due in most cases to requiring long hospitalization periods (weeks to months) and the toxicity (side effects) of administered drugs, in addition to the increasing resistance of the parasites to treatment. It is thus important to develop new drugs and treatments that are less toxic, can overcome drug resistance, and require shorter periods of treatment. These aspects are especially important for the populations of developing countries. It was reported that several phenylpropanoid-based secondary metabolites manifest interesting antileishmanial activities and are used by various indigenous people to treat leishmaniasis. In this chapter, the authors shed some light on the various biological activities of phenylpropanoid natural products, with the main focus being on their possible applications in the context of antileishmanial treatment.


Asunto(s)
Antiprotozoarios , Leishmaniasis , Lignanos , Preparaciones Farmacéuticas , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Humanos , Leishmaniasis/tratamiento farmacológico , Lignanos/farmacología , Lignanos/uso terapéutico , Fenoles/farmacología , Fenoles/uso terapéutico
3.
Chem Biol Interact ; 339: 109429, 2021 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-33713644

RESUMEN

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Treatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. The search for new therapeutic agents from natural sources has been a constant for the treatment of diseases such as leishmaniasis. The objective of this study was to evaluate the biological activity of Eugenia piauhiensis Vellaff. essential oil (EpEO) and its major constituent γ-elemene on promastigote and amastigote forms of Leishmania (Leishmania) amazonensis, its cytotoxicity, and possible mechanisms of action. EpEO was more active (IC50 6.43 ± 0.18 µg/mL) against promastigotes than γ-elemene [9.82 ± 0.15 µg/mL (48.05 ± 0.73 µM)] and the reference drug miltefosine [IC50 17.25 ± 0.26 µg/mL (42.32 ± 0.64 µM)]. EpEO and γ-elemene exhibited low cytotoxicity against J774.A1 macrophages, with CC50 225.8 ± 3.57 µg/mL and 213.21 ± 3.3 µg/mL (1043 ± 16.15 µM), respectively. Additionally, EpEO and γ-elemene present direct activity against the parasite, decreasing plasma membrane integrity. EpEO and γ-elemene also proved to be even more active against intracellular amastigotes of the parasite [IC50 4.59 ± 0.07 µg/mL and 8.06 ± 0.12 µg/mL (39.44 ± 0.59 µM)], respectively), presenting indirect effects through macrophage activity modulation. Anti-amastigote activity was associated with increased TNF-α, IL-12, NO, and ROS levels. In conclusion, our results suggest EpEO and γ-elemene as promising candidates for new drug development against leishmaniasis.


Asunto(s)
Antiprotozoarios/farmacología , Membrana Celular/efectos de los fármacos , Eugenia/química , Inmunomodulación/efectos de los fármacos , Leishmania mexicana/efectos de los fármacos , Aceites Volátiles/farmacología , Sesquiterpenos/farmacología , Animales , Línea Celular , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/parasitología , Macrófagos/parasitología , Ratones , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología
4.
Nat Commun ; 12(1): 1244, 2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33623024

RESUMEN

Differentiation between distinct stages is fundamental for the life cycle of intracellular protozoan parasites and for transmission between hosts, requiring stringent spatial and temporal regulation. Here, we apply kinome-wide gene deletion and gene tagging in Leishmania mexicana promastigotes to define protein kinases with life cycle transition roles. Whilst 162 are dispensable, 44 protein kinase genes are refractory to deletion in promastigotes and are likely core genes required for parasite replication. Phenotyping of pooled gene deletion mutants using bar-seq and projection pursuit clustering reveal functional phenotypic groups of protein kinases involved in differentiation from metacyclic promastigote to amastigote, growth and survival in macrophages and mice, colonisation of the sand fly and motility. This unbiased interrogation of protein kinase function in Leishmania allows targeted investigation of organelle-associated signalling pathways required for successful intracellular parasitism.


Asunto(s)
Diferenciación Celular , Leishmania mexicana/citología , Leishmania mexicana/enzimología , Animales , Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Supervivencia Celular , Femenino , Flagelos/enzimología , Eliminación de Gen , Leishmaniasis/parasitología , Leishmaniasis/patología , Ratones Endogámicos BALB C , Modelos Biológicos , Mutación/genética , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteoma/metabolismo , Psychodidae/parasitología
5.
Adv Protein Chem Struct Biol ; 123: 73-93, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33485489

RESUMEN

Autophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/destroy hazardous substances, proteins, degenerating organelles and recycling nutrients. It plays an important role is cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Being an intra-cellular pathogen, the cell mediated response is the only alternative for adaptive immunity against Leishmania in host. Pro-inflammatory cytokines IL12 and TNFα generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. In the present chapter, through systems biology approach, we are trying to decipher the role of pro-inflammatory and anti-inflammatory cytokine in autophagy during leishmanial infection. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNFα and IL6 etc. Among them TNFα, causes the activation of PI3P through a series of events, which results in activation of autophagic machinery, whereas, IL10 through ATG9 and mTOR activation, inhibits autophagy. The mathematical modeling of these pathways shows that, ATG9-PI3P act as a negative feedback loop in autophagic machinery of leishmaniasis.


Asunto(s)
Proteínas Relacionadas con la Autofagia/inmunología , Autofagia/inmunología , Homeostasis/inmunología , Leishmania/inmunología , Leishmaniasis/inmunología , Modelos Inmunológicos , Células Th2/inmunología , Citocinas/inmunología , Humanos
6.
Parasit Vectors ; 14(1): 36, 2021 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-33422141

RESUMEN

BACKGROUND: Zoonotic visceral leishmaniasis by Leishmania infantum is a first-order pathology in canine veterinary clinics in endemic areas. Moreover, canine infections are considered the main reservoir for human disease; despite their importance in the control of the disease within a One Health approach, no scientometric study has been published. Aims of the study included analyzing the impact of canine leishmaniasis (CanL) on the scientific literature, drugs or combinations used, trends in the period from 2000 to 2020 and efficacy criteria employed. METHODS: A Web of Science (WOS)-based analysis of publications on CanL and chemotherapy of the disease in the period 2000-2020 was carried out using a stepwise methodology. Data were analyzed by year, geographical origin, chemical groups, drugs and combinations, and efficacy criteria. RESULTS: Reports on CanL (n = 3324) represented < 16% of all publications on leishmaniasis (n = 20,968), and of these around 18% (n = 596) were related to chemotherapy. Publication records on CanL followed the distribution of the infection by L. infantum in endemic areas although Mediterranean countries were overrepresented in the reports on chemotherapy of CanL. Publications on the main antileishmanial drugs used in clinical practice showed a sustained tendency in the period analyzed. Pentavalent antimonials (SbV), alone or in combination with allopurinol, represented > 50% of all publications on chemotherapy of CanL despite the availability of more recently marketed drugs. CONCLUSIONS: Chemotherapy of CanL still relies on SbV and combinations and to a lesser extent on miltefosine (MIL). Reports on chemotherapy are scarce and mostly publicly funded, and the variability of experimental conditions hampers the direct comparison of the efficacy of drugs, combinations and schedules. The vast majority of reports on efficacy do not include any information on supportive therapy; this reduces the actual value of the studies if intended for the practical management of the disease. Complete reports on the chemotherapy (etiological + symptomatic) would add value to the trials performed.


Asunto(s)
Antiprotozoarios/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Quimioterapia/métodos , Leishmaniasis/tratamiento farmacológico , Alopurinol/uso terapéutico , Anfotericina B/uso terapéutico , Animales , Enfermedades de los Perros/epidemiología , Perros , Combinación de Medicamentos , Humanos , Leishmania infantum , Leishmaniasis/epidemiología , Leishmaniasis Visceral/epidemiología , Leishmaniasis Visceral/terapia , Fosforilcolina/análogos & derivados , Publicaciones
7.
Parasitol Res ; 120(3): 785-796, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33409640

RESUMEN

Leishmania spp. and Trypanosoma cruzi are parasites belonging to the Trypanosomatidae family and the causative agents for two very important neglected tropical diseases (NTDs), namely leishmaniasis and trypanosomiasis, respectively. Together, they affect millions of people worldwide and the number of cases is constantly rising; thus, further effort on identifying and developing non-toxic, affordable and effective new drug is urgently needed to overcome this alarming situation. Exploring natural products from fungal and bacterial origin remains hitherto a valuable approach to find new hits and candidates for the development of new drugs against these protozoal human infections. Endophytes, which are microorganisms (fungal and bacterial) inhabiting plant tissues, represent a promising source, as they hold potential to produce a high number of distinct chemical scaffolds. These structurally diverse natural products have previously been successfully tested against a wide range of pathogenic microorganisms. The present review provides an update of endophytic compounds exerting anti-trypanosomal and anti-leishmanial effects and their predicted pharmacokinetic properties.


Asunto(s)
Antiprotozoarios/farmacología , Bacterias/química , Productos Biológicos/farmacología , Endófitos/química , Hongos/química , Leishmania/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Animales , Humanos , Leishmania/fisiología , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/parasitología , Plantas/microbiología , Trypanosoma cruzi/fisiología , Tripanosomiasis/tratamiento farmacológico , Tripanosomiasis/parasitología
8.
PLoS One ; 16(1): e0239171, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33465107

RESUMEN

rIL-10 plays a major role in restricting exaggerated inflammatory and immune responses, thus preventing tissue damage. However, the restriction of inflammatory and immune responses by IL-10 can also favor the development and/or persistence of chronic infections or neoplasms. Dogs that succumb to canine leishmaniasis (CanL) caused by L. infantum develop exhaustion of T lymphocytes and are unable to mount appropriate cellular immune responses to control the infection. These animals fail to mount specific lymphoproliferative responses and produce interferon gamma and TNF-alpha that would activate macrophages and promote destruction of intracellular parasites. Blocking IL-10 signaling may contribute to the treatment of CanL. In order to obtain a tool for this blockage, the present work endeavored to identify the canine casIL-10R1 amino acid sequence, generate a recombinant baculovirus chromosome encoding this molecule, which was expressed in insect cells and subsequently purified to obtain rcasIL-10R1. In addition, rcasIL-10R1 was able to bind to homologous IL-10 and block IL-10 signaling pathway, as well as to promote lymphoproliferation in dogs with leishmaniasis caused by L. infantum.


Asunto(s)
Interleucina-10/metabolismo , Leishmaniasis/tratamiento farmacológico , Receptores de Interleucina-10/metabolismo , Animales , Línea Celular , Citocinas/metabolismo , Enfermedades de los Perros/genética , Perros , Femenino , Inmunidad Celular/inmunología , Inmunidad Celular/fisiología , Interferón gamma/genética , Interleucina-10/agonistas , Interleucina-12/genética , Leishmania infantum/inmunología , Leishmania infantum/patogenicidad , Leishmaniasis/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Receptores de Interleucina-10/efectos de los fármacos , Transducción de Señal , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa
10.
Washington, D.C.; PAHO; 2020-12-23.
en Inglés | PAHO-IRIS | ID: phr-53166

RESUMEN

In the Region of the Americas, the leishmaniases are a group of diseases caused by various species of Leishmania, which cause a set of clinical syndromes in infected humans that can involve the skin, mucosa, and visceral organs. The spectrum of clinical disease is varied and depends on the interaction of several factors related to the parasite, the vector, and the host. Cutaneous leishmaniasis is the form most frequently reported in the Region and nearly 90% of cases present single or multiple localized lesions. Other cutaneous clinical forms, such as disseminated and diffuse cutaneous leishmaniasis, are more difficult to treat and relapses are common. The mucosal form is serious because it can cause disfigurement and severe disability if not diagnosed and treated early on. Visceral leishmaniasis is the most severe form, as it can cause death in up to 90% of untreated people. In the Americas, clinical differences can be frequently found between endemic countries, mainly in the cutaneous form. Furthermore, many other diseases can be confused clinically with the different presentations of leishmaniasis and this is one of the greatest challenges for diagnosticians of the disease, who must also be aware of epidemiological reports and the patient’s clinical history. This Interactive Atlas of Leishmaniasis in the Americas: Clinical Aspects and Differential Diagnosis is a joint effort of the Pan American Health Organization, experts on this subject, and other collaborators, with support from the Federico Lleras Acosta University Hospital Dermatology Center of Colombia and the health ministries of the countries of the Region. This is an important and innovative publication that takes a practical approach to the subject, allowing professionals to interactively search for and study photographs and illustrations that reflect their daily work in the health services. The atlas discusses the main concepts and knowledge about leishmaniasis in the Americas, illustrating the clinical situation of these diseases in 10 endemic countries, through 1,029 photographs and illustrations that can be viewed on smartphones, tablets, and desktop or laptop computers. We believe the material will be valuable for all students and professionals at all levels of health care, including those in other continents, when treating patients infected in the Americas.


Asunto(s)
Leishmaniasis , Enfermedades de la Piel , Enfermedades Transmisibles , Américas , Leishmaniasis Mucocutánea , Leishmaniasis Cutánea , Leishmaniasis Visceral
11.
Informe de Leishmanioses;9OPAS/CDE/VT/20-0041.
Monografía en Portugués | PAHO-IRIS | ID: phr-53091

RESUMEN

Nas Américas, as leishmanioses são um problema de saúde pública por sua magnitude e distribuição geográfica e por produzir formas clínicas que podem causar morte, invalidez e mutilação. Nos últimos anos, a Organização Pan-Americana da Saúde (OPAS) - de acordo com o mandato conferido na Iniciativa da OPAS para a eliminação de doenças: política para aplicar um enfoque integrado e sustentável às doenças transmissíveis na Região das América (Resolução CD57/7, aprovada pelo Conselho Diretivo da OPAS em 2019) e de acordo com o roteiro para doenças tropicais negligenciadas 2021-2030 (publicado pela Organização Mundial da Saúde em 2020) - tem apoiado a países endêmicos, com os quais tem desenvolvido iniciativas conjuntas em prol do fortalecimento das ações de vigilância e controle, com o objetivo de reduzir as formas graves da doença, por meio do acesso ao diagnóstico precoce, ao tratamento adequado de casos e redução do contato entre pessoas e vetores. A organização dos serviços, o fortalecimento do conhecimento e da capacidade técnica dos profissionais em diagnóstico e tratamento, bem como o fortalecimento das capacidades entomológicas e do sistema de vigilância para disponibilizar informação atualizada, são medidas que vem sendo implementadas e impulsionadas nas Américas. Este informe apresenta a situação epidemiológica da leishmaniose na Região, por meio de uma análise detalhada dos dados correspondentes a 2019, reportados ao Sistema de Informação Regional de Leishmaniose nas Américas (SisLeish), bem como infográficos dos países endêmicos.


Asunto(s)
Leishmaniasis , Leishmaniasis Visceral , Leishmaniasis Mucocutánea , Zoonosis , Enfermedades Desatendidas , Enfermedades Transmisibles , Vigilancia , Monitoreo Epidemiológico , Américas
12.
Leishmaniases Report;9PAHO/CDE/VT/20-0041.
Monografía en Inglés | PAHO-IRIS | ID: phr-53090

RESUMEN

In the Americas, leishmaniasis are a public health problem due to their magnitude and geographic distribution and because they produce clinical forms that can cause death, disability, and mutilation. In recent years, the Pan American Health Organization (PAHO)—in accordance with the mandate conferred in the PAHO initiative for disease elimination: policy for an Integrated Sustainable Approach to Communicable Diseases in the Americas (Resolution CD57/7, approved by the Directing Council of PAHO in 2019) and in line with the roadmap for neglected tropical diseases 2021-2030 (published by the World Health Organization in 2020)—has supported endemic countries, with which it has developed joint initiatives in favor of strengthening surveillance and control actions, with the goal of reducing severe forms of the disease, through access to early diagnosis, adequate treatment of cases and reduction of contact between people and vectors. The organization of services, the strengthening of knowledge and the technical capacity of professionals in diagnosis and treatment, as well as the strengthening of entomological capacities and the surveillance system to provide updated information, are measures that have been implemented and promoted in the Americas. This report presents the epidemiological situation of leishmaniasis in the Region, through a detailed analysis of the data corresponding to 2019, reported to the Regional Information System of Leishmaniasis in the Americas (SisLeish), as well as infographics of the endemic countries.


Asunto(s)
Leishmaniasis , Leishmaniasis Visceral , Leishmaniasis Mucocutánea , Enfermedades Transmisibles , Zoonosis , Monitoreo Epidemiológico , Enfermedades Desatendidas , Vigilancia , Américas
13.
Informe de Leishmaniasis;9OPS/CDE/VT/20-0041.
Monografía en Español | PAHO-IRIS | ID: phr-53089

RESUMEN

En las Américas, las leishmaniasis son un problema de salud pública debido a su magnitud y distribución geográfica y a que producen formas clínicas que pueden causar muerte, incapacidad y mutilaciones. En los últimos años, la Organización Panamericana de la Salud (OPS) —de conformidad con el mandato conferido en la Iniciativa de la OPS para la eliminación de enfermedades: política para aplicar un enfoque integrado y sostenible de las enfermedades transmisibles en la Región de las Américas (resolución CD57/7, aprobada por el Consejo Directivo de la OPS en el 2019) y en consonancia con la hoja de ruta para las enfermedades tropicales desatendidas 2021-2030 (publicada por la Organización Mundial de la Salud en el 2020)— ha prestado su apoyo a los países endémicos, con los que ha desplegado iniciativas conjuntas en favor del fortalecimiento de las acciones de vigilancia y control, con el objetivo de reducir las formas graves de la enfermedad, a través del acceso al diagnóstico temprano, el tratamiento adecuado de los casos y la reducción del contacto entre las personas y los vectores. La organización de los servicios, el fortalecimiento del conocimiento y la capacidad técnica de los profesionales en el diagnóstico y tratamiento, así como el fortalecimiento de las capacidades entomológicas y del sistema de vigilancia para facilitar información actualizada, son medidas que se han puesto en marcha e impulsado en las Américas. Este informe presenta la situación epidemiológica de las leishmaniasis en la Región, mediante un análisis detallado de los datos correspondientes al 2019, notificados al Sistema de Información Regional de las Leishmaniasis en la Américas (SisLeish), así como infografías de los países endémicos.


Asunto(s)
Leishmaniasis , Enfermedades Transmisibles , Enfermedades Desatendidas , Zoonosis , Vigilancia , Leishmaniasis Mucocutánea , Leishmaniasis Visceral , Monitoreo Epidemiológico , Américas
14.
PLoS Negl Trop Dis ; 14(12): e0008967, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33370303

RESUMEN

Phlebotomine sand flies employ an elaborate system of pheromone communication wherein males produce pheromones that attract other males to leks (thus acting as an aggregation pheromone) and females to the lekking males (sex pheromone). In addition, the type of pheromone produced varies among populations. Despite the numerous studies on sand fly chemical communication, little is known of their chemosensory genome. Chemoreceptors interact with chemicals in an organism's environment to elicit essential behaviors such as the identification of suitable mates and food sources. Thus, they play important roles during adaptation and speciation. Major chemoreceptor gene families, odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs) together detect and discriminate the chemical landscape. Here, we annotated the chemoreceptor repertoire in the genomes of Lutzomyia longipalpis and Phlebotomus papatasi, major phlebotomine vectors in the New World and Old World, respectively. Comparison with other sequenced Diptera revealed a large and unique expansion where over 80% of the ~140 ORs belong to a single, taxonomically restricted clade. We next conducted a comprehensive analysis of the chemoreceptors in 63 L. longipalpis individuals from four different locations in Brazil representing allopatric and sympatric populations and three sex-aggregation pheromone types (chemotypes). Population structure based on single nucleotide polymorphisms (SNPs) and gene copy number in the chemoreceptors corresponded with their putative chemotypes, and corroborate previous studies that identified multiple populations. Our work provides genomic insights into the underlying behavioral evolution of sexual communication in the L. longipalpis species complex in Brazil, and highlights the importance of accounting for the ongoing speciation in central and South American Lutzomyia that could have important implications for vectorial capacity.


Asunto(s)
Células Quimiorreceptoras/metabolismo , Proteínas de Insectos/genética , Leishmaniasis/prevención & control , Leishmaniasis/transmisión , Phlebotomus/parasitología , Atractivos Sexuales/química , Animales , Brasil , Femenino , Insectos Vectores/parasitología , Leishmania , Masculino , Phlebotomus/genética , Phlebotomus/fisiología , Polimorfismo de Nucleótido Simple/genética
16.
Mol Immunol ; 127: 95-106, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32949849

RESUMEN

Leishmania infantum infection may cause visceral leishmaniasis (VL), a fatal disease having worldwide distribution, that may be silent or asymptomatic. The latter indicates that immunity is naturally developed in some individuals, and, therefore, a vaccine against VL would be possible. Molecular mechanisms of gene expression are being understood in Leishmania, and this knowledge may be useful for vaccine development. The aim of this study was developing an attenuated strain by regulating the expression of toxic proteins in a stage specific manner. For that purpose, the 3' UTR of an amastin gene, known by its increased expression in the amastigote phase, was selected for direct the expression of exogenous proteins. This construct (pFL-AMA), firstly, was proved effective for the expression of mCherry specifically in the intracellular form of L. infantum, as demonstrated by fluorescence microscopy, flow cytometry and Western blotting. Afterwards, mCherry coding sequence was replaced, in the pFL-AMA plasmid, by either egg avidin or the active form of bovine trypsin. Viability of transfected parasites was evaluated in promastigote axenic cultures and in in vitro infection of macrophages. Both lines of transfected parasites showed a limited capacity to multiply inside macrophages. BALB/c mice were inoculated intraperitoneally (i.p.) with a single dose consisting of 2 × 106L. infantum promastigotes transfected with plasmids bearing the toxic genes. After 10 weeks post-inoculation, no parasites were recovered by limiting dilution in either liver or spleen, but a specific immunological response was detected. The immunization with transfected parasites induced cellular and humoral immune responses with activation of TCD4+, TCD8+ and B cells, having a TH1-type response with increased levels of pro-inflammatory cytokines such as IFN-γ, TNF-α and IL-6. In parallel groups of mice, a challenge consisting on 1 × 106 virulent parasites of either L. infantum (inoculated i.p.) or L. amazonensis subcutaneously (s.c.) was performed. Vaccinated mice, challenged with L. infantum, showed lower parasite burdens in liver, spleen and bone marrow than infected mice with WT L. infantum (non-vaccinated); similarly, vaccinated mice developed smaller footpad inflammation than control group. These data support this strategy as an efficient immunization system aimed to the development of vaccines against different forms of leishmaniasis.


Asunto(s)
Leishmania infantum/fisiología , Leishmania/fisiología , Leishmaniasis/prevención & control , Leishmaniasis/parasitología , Plásmidos/metabolismo , Toxinas Biológicas/metabolismo , Transfección , Animales , Femenino , Regulación de la Expresión Génica , Humanos , Inmunidad Celular , Inmunidad Humoral , Inmunización , Leishmania/patogenicidad , Leishmania infantum/crecimiento & desarrollo , Leishmania infantum/patogenicidad , Leishmaniasis/inmunología , Estadios del Ciclo de Vida , Ratones Endogámicos BALB C , Parásitos/metabolismo , Parásitos/patogenicidad , Proteínas Protozoarias/metabolismo , Virulencia
17.
PLoS One ; 15(9): e0238933, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32966326

RESUMEN

Serum levels of interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 17 (IL-17), interferon gamma (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin 1ß (IL-1ß), cytokines involved in the immune response, were investigated in 75 Leishmania-positive blood donors living in endemic areas. Based on their status in 2011 and 2015, the subjects were clustered into three groups: positive for at least one diagnostic method in both years, but lacking clinical progression to disease (G1); positive on at least one method in 2011 but negative in 2015 (G2); negative on all methods in both years (G3). Donors were interviewed for sociodemographic data collection and underwent clinical evaluation and laboratory tests. Serum cytokines were quantified using a CBA Flex set (BD Biosciences). Significant differences were found for all the cytokines evaluated, with lower concentrations in consistently Leishmania-negative individuals. The exception was IFN-γ, with similar levels among all donors. No changes consistent with active disease were observed in the laboratory results for Leishmania-positive donors who underwent clinical evaluation, none of whom progressed to disease. This suggests that infection control is associated with serum IL-17 levels. Resolution of Leishmania infection in positive donors may be related to high levels of IL-17 and low levels of IL-10, highlighting the role played by IL-17 in asymptomatic Leishmania-infected individuals.


Asunto(s)
Donantes de Sangre/estadística & datos numéricos , Citocinas/sangre , Leishmania/inmunología , Leishmaniasis/inmunología , Adulto , Enfermedades Asintomáticas , Femenino , Humanos , Interleucina-10/sangre , Interleucina-17/sangre , Leishmaniasis/sangre , Masculino , Persona de Mediana Edad , Regulación hacia Arriba , Adulto Joven
18.
Mem Inst Oswaldo Cruz ; 115: e200220, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32935751

RESUMEN

BACKGROUND: The Nyssomyia genus and Lutzomyia subgenus include medical important species that are Latin American leishmaniases vectors. Little is known about the phylogenetic relationships of closely-related species in each of these taxonomic groups that are morphologically indistinguishable or differentiated by very subtle details. OBJECTIVES: We inferred the phylogenetic relationships of closely-related species within both the Nyssomyia genus and the Lutzomyia subgenus using a cytochrome c oxidase subunit I (COI) fragment. METHODS: The sampling was carried out from 11 Argentinean localities. For genetic analyses, we used GenBank sequences in addition to our sequences from Argentina. Kimura 2-parameter (K2P) genetic distance and nucleotide divergence (Da) was calculated between closely-related species of Nyssomyia genus, Lutzomyia subgenus and between clades of Lutzomyia longipalpis complex. FINDINGS: The K2P and Da values within species of Nyssomyia genus and Lutzomyia subgenus were lower than the divergence detected between clades of Lu. longipalpis complex. The haplotype network analyses within Lutzomyia subgenus showed shared haplotypes between species, contrary to Nyssomyia genus with none haplotype shared. Bayesian inference within Nyssomyia genus presented structuring by species. MAIN CONCLUSIONS: This study evidences the phylogenetic proximity among closely-related species within Nyssomyia genus and Lutzomyia subgenus. The COI sequences of Nyssomyia neivai derived from the present study are the first available in GenBank.


Asunto(s)
Psychodidae/clasificación , Psychodidae/genética , Animales , Argentina , Secuencia de Bases , Teorema de Bayes , Leishmaniasis , Filogenia , Reacción en Cadena de la Polimerasa/métodos , Análisis de Secuencia de ADN/métodos
19.
Washington, D.C.; OPS; 2020-09-09.
en Español | PAHO-IRIS | ID: phr-52645

RESUMEN

El Atlas interactivo de leishmaniasis en las Américas: aspectos clínicos y diagnósticos diferenciales es una publicación innovadora en la que se abordan los principales conceptos, conocimientos y diferencias clínicas de las leishmaniasis en distintos países endémicos de la Región de las Américas. Además, presenta las principales enfermedades de la piel y las mucosas que deben considerarse en el diagnóstico diferencial de las diversas manifestaciones clínicas de las leishmaniasis, lo cual representa uno de los principales desafíos para los profesionales responsables del diagnóstico de la enfermedad.Esta publicación es el resultado de un trabajo conjunto de la Organización Panamericana de la Salud (OPS) con expertos y colaboradores en el tema, que ha contado con el apoyo del Hospital Universitario Centro Dermatológico Federico Lleras Acosta de Colombia y de los Ministerios de Salud de los Estados Miembros de la OPS. El objetivo de esta obra es facilitar a los profesionales de salud la posibilidad de buscar, conocer y analizar de forma interactiva las 1.029 fotografías e ilustraciones de leishmaniasis y de las 55 principales enfermedades que se consideran en el diagnostico diferencial. Esperamos que sea de gran valor para estudiantes, profesores, investigadores y profesionales del sistema de atención de salud de nuestra Región y de todos los demás continentes cuando atiendan pacientes infectados en las Américas.


Asunto(s)
Leishmaniasis , Enfermedades de la Piel , Enfermedades Transmisibles , Américas
20.
Public Health ; 185: 196-198, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32645507

RESUMEN

OBJECTIVES: The main purpose of this study was to explore the reasons behind the late presentation of female patients with leishmaniasis to the clinic. STUDY DESIGN: A descriptive study design and qualitative method were used in this study. METHODS: For information generation, two focus group discussions and three in-depth interviews were conducted with healthcare providers. RESULTS: Many factors, including socio-economic status, lack of knowledge about the disease (i.e. signs and symptoms, transmission, prevention and treatment), the use of traditional or local treatment methods and lack of female healthcare providers, contribute to the late presentation of patients with leishmaniasis to the clinic. This late presentation of patients with leishmaniasis, especially in women, can result in damage to the body tissue, resulting in life-long scars that carry social stigmas. CONCLUSIONS: Leishmaniasis can result in life-long scars if it is not timely diagnosed and treated. As a result of the scars being highly stigmatised, the social life of patients with leishmaniasis can be impacted, especially for female patients.


Asunto(s)
Cicatriz/epidemiología , Personal de Salud/psicología , Leishmaniasis/epidemiología , Aceptación de la Atención de Salud , Mujeres/psicología , Afganistán/epidemiología , Femenino , Humanos , Entrevistas como Asunto , Masculino , Pobreza , Investigación Cualitativa , Clase Social , Estigma Social
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