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1.
Parasit Vectors ; 17(1): 410, 2024 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-39358814

RESUMEN

BACKGROUND: Phlebotomus papatasi is considered the primary vector of Leishmania major parasites that cause zoonotic cutaneous leishmaniasis (ZCL) in the Middle East and North Africa. Phlebotomus papatasi populations have been studied extensively, revealing the existence of different genetic populations and subpopulations over its large distribution range. Genetic diversity and population structure analysis using transcriptome microsatellite markers is important to uncover the vector distribution dynamics, essential for controlling ZCL in endemic areas. METHODS: In this study, we investigated the level of genetic variation using expressed sequence tag-derived simple sequence repeats (EST-SSRs) among field and colony P. papatasi samples collected from 25 different locations in 11 countries. A total of 302 P. papatasi sand fly individuals were analyzed, including at least 10 flies from each region. RESULTS: The analysis revealed a high-level population structure expressed by five distinct populations A through E, with moderate genetic differentiation among all populations. These genetic differences in expressed genes may enable P. papatasi to adapt to different environmental conditions along its distribution range and likely affect dispersal. CONCLUSIONS: Elucidating the population structuring of P. papatasi is essential to L. major containment efforts in endemic countries. Moreover, the level of genetic variation among these populations may improve our understanding of Leishmania-sand fly interactions and contribute to the efforts of vaccine development based on P. papatasi salivary proteins.


Asunto(s)
Variación Genética , Insectos Vectores , Repeticiones de Microsatélite , Phlebotomus , Transcriptoma , Animales , Phlebotomus/genética , Phlebotomus/parasitología , Insectos Vectores/parasitología , Insectos Vectores/genética , Leishmania major/genética , Leishmaniasis Cutánea/prevención & control , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/transmisión , Etiquetas de Secuencia Expresada , Vacunas contra la Leishmaniasis/genética , Vacunas contra la Leishmaniasis/inmunología , Femenino
2.
Genome Biol Evol ; 16(9)2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39224065

RESUMEN

Sand flies infect more than 1 million people annually with Leishmania parasites and other bacterial and viral pathogens. Progress in understanding sand fly adaptations to xenobiotics has been hampered by the limited availability of genomic resources. To address this gap, we sequenced, assembled, and annotated the transcriptomes of 11 phlebotomine sand fly species. Subsequently, we leveraged these genomic resources to generate novel evolutionary insights pertaining to their adaptations to xenobiotics, including those contributing to insecticide resistance. Specifically, we annotated over 2,700 sand fly detoxification genes and conducted large-scale phylogenetic comparisons to uncover the evolutionary dynamics of the five major detoxification gene families: cytochrome P450s (CYPs), glutathione-S-transferases (GSTs), UDP-glycosyltransferases (UGTs), carboxyl/cholinesterases (CCEs), and ATP-binding cassette (ABC) transporters. Using this comparative approach, we show that sand flies have evolved diverse CYP and GST gene repertoires, with notable lineage-specific expansions in gene groups evolutionarily related to known xenobiotic metabolizers. Furthermore, we show that sand flies have conserved orthologs of (i) CYP4G genes involved in cuticular hydrocarbon biosynthesis, (ii) ABCB genes involved in xenobiotic toxicity, and (iii) two primary insecticide targets, acetylcholinesterase-1 (Ace1) and voltage gated sodium channel (VGSC). The biological insights and genomic resources produced in this study provide a foundation for generating and testing hypotheses regarding the molecular mechanisms underlying sand fly adaptations to xenobiotics.


Asunto(s)
Evolución Molecular , Resistencia a los Insecticidas , Insecticidas , Filogenia , Psychodidae , Animales , Psychodidae/genética , Resistencia a los Insecticidas/genética , Insecticidas/farmacología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Genómica , Inactivación Metabólica/genética , Xenobióticos/metabolismo
3.
Sci Data ; 11(1): 918, 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39181902

RESUMEN

Phlebotomine sand flies are the vectors of leishmaniasis, a neglected tropical disease. High-quality reference genomes are an important tool for understanding the biology and eco-evolutionary dynamics underpinning disease epidemiology. Previous leishmaniasis vector reference sequences were limited by sequencing technologies available at the time and inadequate for high-resolution genomic inquiry. Here, we present updated reference assemblies of two sand flies, Phlebotomus papatasi and Lutzomyia longipalpis. These chromosome-level assemblies were generated using an ultra-low input library protocol, PacBio HiFi long reads, and Hi-C technology. The new P. papatasi reference has a final assembly span of 351.6 Mb and contig and scaffold N50s of 926 kb and 111.8 Mb, respectively. The new Lu. longipalpis reference has a final assembly span of 147.8 Mb and contig and scaffold N50s of 1.09 Mb and 40.6 Mb, respectively. Benchmarking Universal Single-Copy Orthologue (BUSCO) assessments indicated 94.5% and 95.6% complete single copy insecta orthologs for P. papatasi and Lu. longipalpis. These improved assemblies will serve as an invaluable resource for future genomic work on phlebotomine sandflies.


Asunto(s)
Genoma de los Insectos , Psychodidae , Animales , Psychodidae/genética , Phlebotomus/genética , Phlebotomus/clasificación , Insectos Vectores/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN
4.
Comp Med ; 74(3): 148-155, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-39107941

RESUMEN

Leishmaniasis, a disease of global relevance, results from infection with the protozoan parasite, Leishmania, which is transmitted to susceptible hosts through the bite of sand flies. Multiple forms of leishmaniasis may occur, including cutaneous, mucocutaneous, and visceral. Research with animal models remains an important approach to help define basic pathophysi- ologic processes associated with infection and disease. In this regard, mice and hamsters represent the most commonly used models. The severity of leishmaniasis in animal models depends on several factors, including genotype of the host and parasite and the dose and route of administration of the parasite to the host, and severity of outcome may range from subclinical to severe illness. This review provides basic background on leishmaniasis, relevant animal models, the pathophysiology and clinical signs in animals used as models of leishmaniasis, and general approaches to mitigate risk to personnel.


Asunto(s)
Modelos Animales de Enfermedad , Leishmaniasis , Animales , Ratones , Cricetinae , Humanos , Leishmania
5.
Methods Mol Biol ; 2802: 573-586, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38819572

RESUMEN

The Eukaryotic Pathogen, Vector and Host Informatics Resources ( VEuPathDB.org ) provide free online access to omic data from eukaryotic protozoan and fungal pathogens, arthropod vectors of disease, and host responses to pathogen infection. The goal of VEuPathDB is to make data easily accessible, findable, and importantly, re-usable by laboratory scientists. All integrated data and analyses follow standard workflows and methods to ensure data accuracy and enable data interoperability. Integrated data include genomes and annotation, transcriptomic (e.g., single-cell/bulk RNA-sequence and microarray data), proteomic (e.g., mass spectrometry evidence and quantitative data), isolate sequencing data used for variant calling and copy number variation determination, epigenomics, whole-genome phenotyping data (e.g., CRISPR screens and large-scale imaging and subcellular localization data), etc. Standard analyses provide additional data such as InterPro domains, signal peptide and transmembrane domain predictions, and metabolic pathways. Comparative genomic analysis in VEuPathDB is facilitated by leveraging orthology to enable the transformation of results between organisms and identifying genes with specific phyletic patterns. In addition, synteny between genomes is facilitated by shading orthologs across species and strains. Accessibility to and re-usability of the data is made possible through specialized searches and a graphical search strategy system that enables scientists to build in silico experiments combining results from multiple experiments with diverse data types.


Asunto(s)
Biología Computacional , Biología Computacional/métodos , Genómica/métodos , Proteómica/métodos , Programas Informáticos , Animales , Bases de Datos Genéticas , Humanos , Interacciones Huésped-Patógeno/genética , Internet
6.
Genetics ; 227(1)2024 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-38529759

RESUMEN

FungiDB (https://fungidb.org) serves as a valuable online resource that seamlessly integrates genomic and related large-scale data for a wide range of fungal and oomycete species. As an integral part of the VEuPathDB Bioinformatics Resource Center (https://veupathdb.org), FungiDB continually integrates both published and unpublished data addressing various aspects of fungal biology. Established in early 2011, the database has evolved to support 674 datasets. The datasets include over 300 genomes spanning various taxa (e.g. Ascomycota, Basidiomycota, Blastocladiomycota, Chytridiomycota, Mucoromycota, as well as Albuginales, Peronosporales, Pythiales, and Saprolegniales). In addition to genomic assemblies and annotation, over 300 extra datasets encompassing diverse information, such as expression and variation data, are also available. The resource also provides an intuitive web-based interface, facilitating comprehensive approaches to data mining and visualization. Users can test their hypotheses and navigate through omics-scale datasets using a built-in search strategy system. Moreover, FungiDB offers capabilities for private data analysis via the integrated VEuPathDB Galaxy platform. FungiDB also permits genome improvements by capturing expert knowledge through the User Comments system and the Apollo genome annotation editor for structural and functional gene curation. FungiDB facilitates data exploration and analysis and contributes to advancing research efforts by capturing expert knowledge for fungal and oomycete species.


Asunto(s)
Biología Computacional , Bases de Datos Genéticas , Hongos , Internet , Oomicetos , Oomicetos/genética , Hongos/genética , Biología Computacional/métodos , Genoma Fúngico , Genómica/métodos , Programas Informáticos
7.
Parasit Vectors ; 17(1): 19, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38217054

RESUMEN

BACKGROUND: Understanding aspects related to the physiology and capacity of vectors is essential for effectively controlling vector-borne diseases. The sand fly Lutzomyia longipalpis has great importance in medical entomology for disseminating Leishmania parasites, the causative agent of Leishmaniasis, one of the main neglected diseases listed by the World Health Organization (WHO). In this respect, it is necessary to evaluate the transmission potential of this species and the success of vector control interventions. Near-infrared spectroscopy (NIRS) has been used to estimate the age of mosquitoes in different conditions (laboratory, semi-field, and conservation), taxonomic analysis, and infection detection. However, no studies are using NIRS for sand flies. METHODS: In this study, we developed analytic models to estimate the age of L. longipalpis adults under laboratory conditions, identify their copulation state, and evaluate their gonotrophic cycle and diet. RESULTS: Sand flies were classified with an accuracy of 58-82% in 3 age groups and 82-92% when separating them into young (<8 days) or old (>8 days) insects. The classification between mated and non-mated sandflies was 98-100% accurate, while the percentage of hits of females that had already passed the first gonotrophic cycle was only 59%. CONCLUSIONS: We consider the age and copula estimation results very promising, as they provide essential aspects of vector capacity assessment, which can be obtained quickly and at a lower cost with NIRS.


Asunto(s)
Leishmania , Leishmaniasis , Phlebotomus , Psychodidae , Femenino , Animales , Psychodidae/parasitología , Espectroscopía Infrarroja Corta , Mosquitos Vectores , Leishmania/fisiología
8.
Nucleic Acids Res ; 52(D1): D808-D816, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37953350

RESUMEN

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) is a Bioinformatics Resource Center funded by the National Institutes of Health with additional funding from the Wellcome Trust. VEuPathDB supports >600 organisms that comprise invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Since 2004, VEuPathDB has analyzed omics data from the public domain using contemporary bioinformatic workflows, including orthology predictions via OrthoMCL, and integrated the analysis results with analysis tools, visualizations, and advanced search capabilities. The unique data mining platform coupled with >3000 pre-analyzed data sets facilitates the exploration of pertinent omics data in support of hypothesis driven research. Comparisons are easily made across data sets, data types and organisms. A Galaxy workspace offers the opportunity for the analysis of private large-scale datasets and for porting to VEuPathDB for comparisons with integrated data. The MapVEu tool provides a platform for exploration of spatially resolved data such as vector surveillance and insecticide resistance monitoring. To address the growing body of omics data and advances in laboratory techniques, VEuPathDB has added several new data types, searches and features, improved the Galaxy workspace environment, redesigned the MapVEu interface and updated the infrastructure to accommodate these changes.


Asunto(s)
Biología Computacional , Eucariontes , Animales , Biología Computacional/métodos , Invertebrados , Bases de Datos Factuales
9.
PLoS Negl Trop Dis ; 17(1): e0011058, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36656904

RESUMEN

Parasitic diseases caused by kinetoplastid parasites are a burden to public health throughout tropical and subtropical regions of the world. TriTrypDB (https://tritrypdb.org) is a free online resource for data mining of genomic and functional data from these kinetoplastid parasites and is part of the VEuPathDB Bioinformatics Resource Center (https://veupathdb.org). As of release 59, TriTrypDB hosts 83 kinetoplastid genomes, nine of which, including Trypanosoma brucei brucei TREU927, Trypanosoma cruzi CL Brener and Leishmania major Friedlin, undergo manual curation by integrating information from scientific publications, high-throughput assays and user submitted comments. TriTrypDB also integrates transcriptomic, proteomic, epigenomic, population-level and isolate data, functional information from genome-wide RNAi knock-down and fluorescent tagging, and results from automated bioinformatics analysis pipelines. TriTrypDB offers a user-friendly web interface embedded with a genome browser, search strategy system and bioinformatics tools to support custom in silico experiments that leverage integrated data. A Galaxy workspace enables users to analyze their private data (e.g., RNA-sequencing, variant calling, etc.) and explore their results privately in the context of publicly available information in the database. The recent addition of an annotation platform based on Apollo enables users to provide both functional and structural changes that will appear as 'community annotations' immediately and, pending curatorial review, will be integrated into the official genome annotation.


Asunto(s)
Kinetoplastida , Programas Informáticos , Interfaz Usuario-Computador , Proteómica , Genómica/métodos , Biología Computacional/métodos , Bases de Datos Genéticas , Internet
10.
Microbiol Spectr ; 10(6): e0265822, 2022 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-36342284

RESUMEN

Leishmaniasis, a category I neglected tropical disease, is a group of diseases caused by the protozoan parasite Leishmania species with a wide range of clinical manifestations. Current treatment options can be highly toxic and expensive, with drug relapse and the emergence of resistance. Bacteriocins, antimicrobial peptides ribosomally produced by bacteria, are a relatively new avenue for potential antiprotozoal drugs. Particular interest has been focused on enterocin AS-48, with previously proven efficacy against protozoan species, including Leishmania spp. Sequential characterization of enterocin AS-48 has illustrated that antibacterial bioactivity is preserved in linearized, truncated forms; however, minimal domains of AS-48 bacteriocins have not yet been explored against protozoans. Using rational design techniques to improve membrane penetration activity, we designed peptide libraries using the minimal bioactive domain of AS-48 homologs. Stepwise changes to the charge (z), hydrophobicity (H), and hydrophobic dipole moment (µH) were achieved through lysine and tryptophan substitutions and the inversion of residues within the helical wheel, respectively. A total of 480 synthetic peptide variants were assessed for antileishmanial activity against Leishmania donovani. One hundred seventy-two peptide variants exhibited 50% inhibitory concentration (IC50) values below 20 µM against axenic amastigotes, with 60 peptide variants in the nanomolar range. Nine peptide variants exhibited potent activity against intracellular amastigotes with observed IC50 values of <4 µM and limited in vitro host cell toxicity, making them worthy of further drug development. Our work demonstrates that minimal bioactive domains of naturally existing bacteriocins can be synthetically engineered to increase membrane penetration against Leishmania spp. with minimal host cytotoxicity, holding the promise of novel, potent antileishmanial therapies. IMPORTANCE Leishmaniasis is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. There are three primary clinical forms, cutaneous, mucocutaneous, and visceral, with visceral leishmaniasis being fatal if left untreated. Current drug treatments are less than ideal, especially in resource-limited areas, due to the difficult administration and treatment regimens as well as the high cost and the emergence of drug resistance. Identifying potent antileishmanial agents is of the utmost importance. We utilized rational design techniques to synthesize enterocin AS-48 and AS-48-like bacteriocin-based peptides and screened these peptides against L. donovani using a fluorescence-based phenotypic assay. Our results suggest that bacteriocins, specifically these rationally designed AS-48-like peptides, are promising leads for further development as antileishmanial drugs.


Asunto(s)
Antiprotozoarios , Bacteriocinas , Leishmania donovani , Leishmaniasis , Humanos , Bacteriocinas/farmacología , Bacteriocinas/uso terapéutico , Leishmaniasis/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Antiprotozoarios/farmacología
11.
Pest Manag Sci ; 78(7): 2792-2805, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35411662

RESUMEN

BACKGROUND: Leishmaniasis is an infectious parasitic disease caused by pathogens of the genus Leishmania transmitted through the bite of adult female sand flies. To reduce case numbers, it is necessary to combine different control approaches, especially those aimed at the sand fly vectors. Innovative forms of control with the use of attractive sugar baits explored the fact that adult sand flies need to feed on sugars of plant origin. Leishmania parasites develop in the gut of sand flies, interacting with the sugars in the diet of adults. Recent studies have shown that sugar baits containing plant-derived compounds can reduce sand fly survival, the number of parasites per gut, and the percentage of infected sand flies. Several synthetic compounds produced from naphthoquinones and pterocarpans have anti-parasitic activity on Leishmania amazonensis and/or Leishmania infantum in cell culture. This work aimed to assess the inclusion of these compounds in sugar baits for blocking transmission, targeting the development of the Leishmania parasite inside the sand fly vector. RESULTS: We evaluated the attractant or repellent properties of these compounds, as well as of the reference compound N,N'-diethyl-m-toluamide (DEET), in sugar baits. We also observed changes in feeding preference caused by these compounds, looking for anti-feeding or stimulation of ingestion. Pterocarpanquinone L4 and pentamidine showed attractant and repellent properties, respectively. CONCLUSION: Based on the effects in feeding preference and intake volume, pterocarpanquinone L6, and the pyrazole-derived compound P8 were chosen as the most promising compounds for the future development of anti-Leishmania sugar baits. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Asunto(s)
Repelentes de Insectos , Leishmania infantum , Leishmaniasis , Phlebotomus , Psychodidae , Animales , Femenino , Leishmania infantum/fisiología , Leishmaniasis/prevención & control , Psychodidae/parasitología , Psychodidae/fisiología , Azúcares
12.
Nucleic Acids Res ; 50(D1): D898-D911, 2022 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-34718728

RESUMEN

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.


Asunto(s)
Bases de Datos Factuales , Vectores de Enfermedades/clasificación , Interacciones Huésped-Patógeno/genética , Fenotipo , Interfaz Usuario-Computador , Animales , Apicomplexa/clasificación , Apicomplexa/genética , Apicomplexa/patogenicidad , Bacterias/clasificación , Bacterias/genética , Bacterias/patogenicidad , Enfermedades Transmisibles/microbiología , Enfermedades Transmisibles/parasitología , Enfermedades Transmisibles/patología , Enfermedades Transmisibles/transmisión , Biología Computacional/métodos , Minería de Datos/métodos , Diplomonadida/clasificación , Diplomonadida/genética , Diplomonadida/patogenicidad , Hongos/clasificación , Hongos/genética , Hongos/patogenicidad , Humanos , Insectos/clasificación , Insectos/genética , Insectos/patogenicidad , Internet , Nematodos/clasificación , Nematodos/genética , Nematodos/patogenicidad , Filogenia , Virulencia , Flujo de Trabajo
13.
Curr Opin Insect Sci ; 50: 100860, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34864248

RESUMEN

VectorBase (VectorBase.org) is part of the VEuPathDB Bioinformatics Resource Center, providing free online access to multi-omics and population biology data, focusing on arthropod vectors and invertebrates of importance to human health. VectorBase includes genomics and functional genomics data from bed bugs, biting midges, body lice, kissing bugs, mites, mosquitoes, sand flies, ticks, tsetse flies, stable flies, house flies, fruit flies, and a snail intermediate host. Tools include the Search Strategy system and MapVEu, enabling users to interrogate and visualize diverse 'omics and population-level data using a graphical interface (no programming experience required). Users can also analyze their own private data, such as transcriptomic sequences, exploring their results in the context of other publicly-available information in the database. Help Desk: help@vectorbase.org.


Asunto(s)
Biología Computacional , Culicidae , Animales , Genómica , Humanos , Invertebrados/genética , Mosquitos Vectores
14.
Exp Parasitol ; 220: 107968, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32781093

RESUMEN

The parasitic protozoan Leishmania infantum resides primarily in macrophages throughout mammalian infection. Infection is initiated by deposition of the metacyclic promastigote into the dermis of a mammalian host by the sand fly vector. Promastigotes enter macrophages by ligating surface receptors such as complement receptor 3 (CR3), inducing phagocytosis of the parasite. At the binding site of metacyclic promastigotes, we observed large asymmetrical aggregates of macrophage membrane with underlying actin, resembling membrane ruffles. Actin accumulation was observed at the point of initial contact, before phagosome formation and accumulation of peri-phagosomal actin. Ruffle-like structures did not form during phagocytosis of attenuated promastigotes or during phagocytosis of the intracellular amastigote form of L. infantum. Entry of promastigotes through massive actin accumulation was associated with a subsequent delay in fusion of the parasitophorous vacuole (PV) with the lysosomal markers LAMP-1 and Cathepsin D. Actin accumulation was also associated with entry through CR3, since macrophages from CD11b knockout (KO) mice did not form massive aggregates of actin during phagocytosis of metacyclic promastigotes. Furthermore, intracellular survival of L. infantum was significantly decreased in CD11b KO compared to wild type macrophages, although entry rates were similar. We conclude that both promastigote virulence and host cell CR3 are needed for the formation of ruffle-like membrane structures at the site of metacyclic promastigote phagocytosis, and that formation of actin-rich aggregates during entry correlates with the intracellular survival of virulent promastigotes.


Asunto(s)
Actinas/metabolismo , Leishmania infantum/fisiología , Leishmaniasis Visceral/parasitología , Antígeno de Macrófago-1/fisiología , Fagocitosis/fisiología , Animales , Catepsina D/metabolismo , Membrana Celular/ultraestructura , Cricetinae , Humanos , Leishmania infantum/patogenicidad , Leishmania infantum/ultraestructura , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Macrófagos/parasitología , Masculino , Mesocricetus , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microscopía Confocal , Vacuolas/parasitología , Virulencia
15.
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.
PLoS Negl Trop Dis ; 14(7): e0007489, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32658913

RESUMEN

Phlebotomus papatasi sand flies inject their hosts with a myriad of pharmacologically active salivary proteins to assist with blood feeding and to modulate host defenses. In addition, salivary proteins can influence cutaneous leishmaniasis disease outcome, highlighting the potential of the salivary components to be used as a vaccine. Variability of vaccine targets in natural populations influences antigen choice for vaccine development. Therefore, the objective of this study was to investigate the variability in the predicted protein sequences of nine of the most abundantly expressed salivary proteins from field populations, testing the hypothesis that salivary proteins appropriate to target for vaccination strategies will be possible. PpSP12, PpSP14, PpSP28, PpSP29, PpSP30, PpSP32, PpSP36, PpSP42, and PpSP44 mature cDNAs from field collected P. papatasi from three distinct ecotopes in the Middle East and North Africa were amplified, sequenced, and in silico translated to assess the predicted amino acid variability. Two of the predicted sequences, PpSP12 and PpSP14, demonstrated low genetic variability across the three geographic isolated sand fly populations, with conserved multiple predicted MHCII epitope binding sites suggestive of their potential application in vaccination approaches. The other seven predicted salivary proteins revealed greater allelic variation across the same sand fly populations, possibly precluding their use as vaccine targets.


Asunto(s)
Proteínas de Insectos/genética , Insectos Vectores/genética , Phlebotomus/genética , Proteínas y Péptidos Salivales/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Egipto , Humanos , Proteínas de Insectos/inmunología , Insectos Vectores/inmunología , Jordania , Phlebotomus/inmunología , Proteínas y Péptidos Salivales/inmunología , Alineación de Secuencia
17.
Malariaworld J ; 11: 2, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-34532221

RESUMEN

BACKGROUND: Over the past decade, Cambodia has seen a significant decline in its malaria burden. The government has established the goal of eliminating malaria in the country by 2025. With PMI/USAID support, Cambodia is implementing a package of interventions as part of its efforts. This assessment aimed to describe the cost of malaria elimination activities in Sampov Loun Operational District (OD) between July 2015 and March 2018, to describe the cost per malaria case detected under PMI programming, and to estimate the incremental cost-effectiveness of the elimination programme per Plasmodium falciparum (Pf) or P. vivax (Pv)/Pf mixed case averted under the Cambodia Malaria Elimination Programme (CMEP) and the U.S. President's Malaria Initiative. Opportunity costs of government workers were also assessed to understand the theoretical cost of sustaining this programme through government efforts alone. MATERIALS AND METHODS: We conducted an empirical micro-costing analysis based on elimination activities alone using CMEP internal project implementation data and corresponding epidemiologic data from July 2015 to March 2018 and empirical findings from implementation to date. We then constructed a cost model in Microsoft Excel using empirical data and used a cost-effectiveness decision tree to describe programme effectiveness in the first three years of implementation and to estimate efficacy for the subsequent year. RESULTS: The total cost of malaria elimination activities in Sampov Loun OD from July 2015 to March 2018 was $883,096. The cost per case of malaria detected in 2017 was $1,304. Including opportunity costs for government staff from July 2015 to March 2018, the total cost was $926,000. Under continued CMEP implementation, the projected future total cost of the program would be about $110,000 per year, or $0.64 per Sampov Loun resident. The incremental cost-effectiveness of the elimination programme was $28 for every additional Pf or Pv/Pf mix malaria case averted, compared to the no-CMEP proxy. CONCLUSION: CMEP activities are cost effective compared to the no-CMEP proxy, as shown through an incremental cost-effectiveness of $28 for every additional Pf or Pv/Pf mix malaria case averted. The total cost of the project is 0.93% of the total per capita spending on health in Cambodia and about 5% of all government health expenditure. Continuing investments in malaria will be needed at national level for stewardship and governance and at local level for ensuring programme readiness in case of malaria outbreaks.

18.
Parasit Vectors ; 12(1): 557, 2019 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-31767025

RESUMEN

BACKGROUND: Transmission of malaria in the highlands of Ethiopia is poorly understood and usually attributed to importation by mobile populations or local transmission by Anopheles arabiensis. To characterize and identify Anopheles species present in a highland area of northern Ethiopia, adult and larval collections were performed in Gondar town and the neighboring Senbet Debir village (Dembia district, > 2000 meters above sea level, masl), in addition to Bahir Dar town (capital of Amhara region) and Kumer Aftit village (Metema district, < 2000 masl). METHODS: CDC-light traps were used to collect adult mosquitoes and larval collections were performed from rain pools for rearing into adults for species identification. Collections were made September-March 2016-2018. Adult mosquitoes were identified morphologically and a subset of randomly chosen specimens were identified to species by sequencing the ribosomal DNA internal transcribed spacer region 2 (ITS2) and mitochondrial DNA cytochrome c oxidase subunit 1 (cox1). RESULTS: The primary species of Anopheles identified at elevations higher than 2000 masl was An. cinereus, which was confirmed molecularly by ITS2 and cox1 sequencing. Interestingly, two unknown species were also sequenced, in addition to two specimens of An. pretoriensis. The species collected at sites with elevations less than 2000 masl (Bahir Dar town and Kumer Aftit village) was An. arabiensis. Three Plasmodium falciparum-positive specimens were identified molecularly as An. cinereus. CONCLUSIONS: The presence of Plasmodium-positive An. cinereus in areas greater than 2000 masl incriminates this species as a potential vector contributing to non-peak malaria transmission in Ethiopian highland areas.


Asunto(s)
Anopheles/parasitología , Malaria/transmisión , Mosquitos Vectores/parasitología , Animales , Etiopía , Femenino , Larva/parasitología , Malaria/prevención & control , Plasmodium falciparum , Lluvia
19.
Int J Antimicrob Agents ; 54(4): 496-501, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31323307

RESUMEN

Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The World Health Organization has classed leishmaniasis as a category 1 neglected tropical disease. Leishmaniasis represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. As the use of oral treatment options such as paromomycin and miltefosine has increased, the incidence of disease relapse has increased and drug resistance to antimonials has developed, emphasizing the importance of identifying new chemotherapies. A novel, target-free fluorometric high-throughput screen with an average Z-score of 0.73 +/- 0.13 has been developed to identify small molecules with antileishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80% of parasites, resulting in a hit rate of 2.1%. One hundred and nine molecular scaffolds were represented within the hit compounds, and one scaffold that exhibited potent antileishmanial activity was 2,4-diaminoquinazoline. Host cell toxicity was determined prior to in-vitro infection of human THP-1 macrophages with Leishmania donovani mCherry expressing promastigotes; successful drug treatment was considered when the half maximal inhibitory concentration was <10 µM. BALB/c mice were infected with Leishmania major mCherry promastigotes and treated with small molecules that were successful during in-vitro infections. Several small molecules tested were as efficacious at resolving cutaneous leishmaniasis lesions in mice as known antimonial treatments.


Asunto(s)
Antiprotozoarios/aislamiento & purificación , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento , Leishmania donovani/efectos de los fármacos , Leishmania major/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/farmacología , Modelos Animales de Enfermedad , Femenino , Fluorometría/métodos , Humanos , Ratones Endogámicos BALB C , Recurrencia , Células THP-1/parasitología , Resultado del Tratamiento
20.
Sci Rep ; 9(1): 4421, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30872615

RESUMEN

Aedes aegypti and Anopheles gambiae harbor the causative agents of diseases such as dengue fever and malaria, afflicting human morbidity and mortality worldwide. Given the worldwide emergence of resistance to insecticides, the current mainstay for vector control, identification of alternative modes of action for future insecticides is paramount. The serotonergic (5-HT) system has been documented to impact physiological mechanisms involved in disease transmission, suggesting its potential as a new mode of action target for future insecticide development. Target 5-HT receptors were cloned and expressed in the HEK293 cell line for functional and pharmacological characterization. Manipulation of the 5-HT system through microinjection of compounds suggests its involvement in the modulation of flight performance and blood-feeding behavior. By attenuating these two determinants of vectorial capacity, transmission and burden of disease could effectively be reduced. Considering these positive global health implications, the 5-HT system is a compelling target for the novel insecticide pipeline.


Asunto(s)
Aedes/metabolismo , Anopheles/metabolismo , Conducta Alimentaria/efectos de los fármacos , Vuelo Animal/efectos de los fármacos , Insecticidas/farmacología , Mosquitos Vectores/metabolismo , Receptores de Serotonina/metabolismo , Aedes/efectos de los fármacos , Aedes/parasitología , Animales , Anopheles/efectos de los fármacos , Anopheles/parasitología , Femenino , Resistencia a los Insecticidas , Malaria/tratamiento farmacológico , Malaria/metabolismo , Malaria/parasitología , Mosquitos Vectores/efectos de los fármacos , Mosquitos Vectores/parasitología , Plasmodium malariae/aislamiento & purificación , Receptores de Serotonina/genética
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