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1.
Chem Biol Interact ; 339: 109429, 2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33713644

RESUMO

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.


Assuntos
Antiprotozoários/farmacologia , Membrana Celular/efeitos dos fármacos , Eugenia/química , Imunomodulação/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Óleos Voláteis/farmacologia , Sesquiterpenos/farmacologia , Animais , Linhagem Celular , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Macrófagos/parasitologia , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia
2.
Nat Commun ; 12(1): 1244, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623024

RESUMO

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.


Assuntos
Diferenciação Celular , Leishmania mexicana/citologia , Leishmania mexicana/enzimologia , Animais , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Sobrevivência Celular , Feminino , Flagelos/enzimologia , Deleção de Genes , Leishmaniose/parasitologia , Leishmaniose/patologia , Camundongos Endogâmicos BALB C , Modelos Biológicos , Mutação/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteoma/metabolismo , Psychodidae/parasitologia
3.
Mol Immunol ; 127: 95-106, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32949849

RESUMO

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.


Assuntos
Leishmania infantum/fisiologia , Leishmania/fisiologia , Leishmaniose/prevenção & controle , Leishmaniose/parasitologia , Plasmídeos/metabolismo , Toxinas Biológicas/metabolismo , Transfecção , Animais , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Celular , Imunidade Humoral , Imunização , Leishmania/patogenicidade , Leishmania infantum/crescimento & desenvolvimento , Leishmania infantum/patogenicidade , Leishmaniose/imunologia , Estágios do Ciclo de Vida , Camundongos Endogâmicos BALB C , Parasitos/metabolismo , Parasitos/patogenicidade , Proteínas de Protozoários/metabolismo , Virulência
4.
Trends Parasitol ; 36(9): 785-795, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32713762

RESUMO

Leishmania parasites have the capacity to rapidly adapt to changing environments in their digenetic life cycle which alternates between a vertebrate and an invertebrate host. Emergence of resistance following drug exposure can evoke phenotypic alterations that affect several aspects of parasite fitness in both hosts. Current studies of the impact of resistance are mostly limited to interactions with the mammalian host and characterization of in vitro parasite growth and differentiation. Development in the vector and transmission capacity have been largely ignored. This review reflects on the impact of drug resistance on its spreading potential with specific focus on the use of the sand fly infection model to evaluate parasite development in the vector and the ensuing transmission potential of drug-resistant phenotypes.


Assuntos
Resistência a Medicamentos , Insetos Vetores/parasitologia , Leishmaniose/transmissão , Psychodidae/parasitologia , Animais , Antiparasitários/farmacologia , Humanos , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Leishmaniose/parasitologia , Estágios do Ciclo de Vida/fisiologia
5.
PLoS One ; 15(7): e0236253, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692759

RESUMO

INTRODUCTION: Understanding the feeding behavior and host choice of sand flies provides valuable information on vector-host relationships and elucidates the epidemiological patterns of leishmaniasis transmission. Blood meal analysis studies are essential for estimating the efficiency of pathogen transmission, assessing the relative human disease risk, and assist in identifying the other potential hosts of leishmaniasis. In Sudan and most of East Africa, there are large remaining gaps in knowledge regarding the feeding habits of phlebotomine vectors. The study aimed to identify the blood meal sources and, therefore, the host preferences of the principal vectors Phlebotomus orientalis and Ph. papatasi in leishmaniasis endemic areas of eastern and central Sudan. MATERIALS AND METHODS: Sand flies were collected from two endemic villages in eastern and central Sudan using CDC light traps and sticky traps. The phlebotomine sand flies were morphologically and then molecularly identified. The source of blood meal of the engorged females was determined using a multiplex PCR methodology and specific primers of cytochrome b gene of mitochondrial DNA for human, goat, cow, and dog. The detection of the Leishmania parasite was done using PCR. RESULTS: The total number of collected female phlebotomine sand flies was 180. Morphological identification revealed the abundance of Ph. orientalis 103 (57.2%), Ph. papatasi 42 (23.3%), Ph. bergeroti 31 (17.2%), Ph. rodhaini 2 (1.1%) and Ph. duboscqi 2 (1.1%) in the study sites. Out of the 180 collected, 31 (17%) were blood-fed flies. Three species were blood-fed and molecularly identified: Ph. papatasi (N = 7, 22.6%), Ph. bergeroti (N = 9, 26%), and Ph. orientalis (N = 15, 48.4%). Blood meal analysis revealed human DNA in two Ph. orientalis (6.4%), hence, the anthropophilic index was 13.3%. CONCLUSIONS: Multiplex PCR protocol described here allowed the identification of blood meal sources of many vertebrate species simultaneously. The results indicate that wild-caught Ph. orientalis are anthropophilic in the study areas. Further studies on larger blood-fed sample size are required to validate the potential applications of this technique in designing, monitoring and evaluating control programs, particularly in investigating the potential non-human hosts of leishmaniasis.


Assuntos
Interações Hospedeiro-Patógeno , Insetos Vetores/parasitologia , Leishmaniose/parasitologia , Phlebotomus/fisiologia , Animais , DNA/genética , Feminino , Geografia , Sudão
6.
PLoS One ; 15(6): e0234445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579586

RESUMO

This study aimed to describe the sand fly fauna and detect trypanosomatids in these insects from Casa Branca, state of Minas Gerais, Brazil, an endemic area of both visceral (VL) and tegumentary leishmaniasis (TL). Sand flies were collected bimonthly from May 2013 to July 2014, using automatic light traps exposed for three consecutive nights in peridomiciliary areas of nine houses with previous reports of VL and TL. ITS1-PCR and DNA sequencing were performed for trypanosomatids identification. A total of 16,771 sand flies were collected belonging to 23 species. The most abundant species was Nyssomyia whitmani (Antunes & Coutinho, 1939) (70.9%), followed by Lutzomyia longipalpis (Lutz & Neiva, 1912) (15.2%) and Migonemyia migonei (França, 1920) (9.1%). Leishmania amazonensis DNA was detected in Ny. whitmani (four pools) and Le. braziliensis DNA was detected in Psychodopygus lloydi (one pool). In seven pools of Ny. whitmani and in one pool of Lu. longipalpis positive for Leishmania DNA, the parasite species was not determined due to the low quality of the sequences. Moreover, DNA of Herpetomonas spp. was detected in Ny. whitmani (two pools) and Cortelezzii complex (one pool). DNA of Crithidia spp. was detected in Ny. whitmani and Ps. lloydi (both one pool). Our results suggest that Ny. whitmani may be involved in the transmission of Le. amazonensis in the study area. The molecular detection of Le. amazonensis suggests the presence of this species in a sylvatic cycle between vertebrate and invertebrate hosts in the region of Casa Branca. Our data also reveal the occurrence of other non-Leishmania trypanosomatids in sand flies in Casa Branca District.


Assuntos
Biodiversidade , Insetos Vetores/parasitologia , Leishmania/isolamento & purificação , Phlebotomus/parasitologia , Psychodidae/parasitologia , Animais , Brasil/epidemiologia , DNA de Protozoário/isolamento & purificação , Doenças Endêmicas/prevenção & controle , Feminino , Humanos , Leishmania/genética , Leishmaniose/epidemiologia , Leishmaniose/parasitologia , Leishmaniose/prevenção & controle , Leishmaniose/transmissão , Análise de Sequência de DNA
7.
Rev Bras Parasitol Vet ; 29(2): e003520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520088

RESUMO

Blood samples and swabs from ocular conjunctiva and mouth were obtained from 64 cats. Of 64 serum samples, 19 were positive for Leishmania antibodies by ELISA (29.80%). Eight cats were positive by PCR (12.5%) in swab samples from mouth and/or ocular mucosa. Poor kappa agreement between serological and molecular results (k = 0.16) was obtained. From five positive PCR samples one was L. braziliensis and four were L. infantum. Phylogenetic analysis performed with the five isolates of Leishmania, showed that samples of L. infantum isolated from the cats were phylogenetically close to those isolated from domestic dogs in Brazil, while the L. braziliensis is very similar to the one described in humans in Venezuela. The study demonstrated that, despite high seropositivity for Leishmania in cats living in the study region, poor agreement between serological and molecular results indicate that positive serology is not indicative of Leishmania infection in cats. Parasite DNA can be detected in ocular conjunctiva and oral swabs from cats, indicating that such samples could be used for diagnosis. Results of phylogenetic analyzes show that L. infantum circulating in Brazil is capable of infecting different hosts, demonstrating the parasite's ability to overcome the interspecies barrier.


Assuntos
Doenças do Gato/parasitologia , Leishmania braziliensis/isolamento & purificação , Leishmania infantum/isolamento & purificação , Leishmaniose/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Doenças do Gato/diagnóstico , Gatos , DNA de Protozoário/análise , Ensaio de Imunoadsorção Enzimática/veterinária , Leishmania braziliensis/genética , Leishmania braziliensis/imunologia , Leishmania infantum/genética , Leishmania infantum/imunologia , Leishmaniose/diagnóstico , Filogenia , Reação em Cadeia da Polimerase/veterinária
8.
Parasite Immunol ; 42(7): e12722, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32294247

RESUMO

Leishmaniasis is a neglected infectious disease with clinical presentations ranging from asymptomatic or mild symptoms to chronic infection and eventual death. The mechanisms of disease susceptibility and pathology have been extensively studied, but there are no steadfast rules regarding leishmaniasis. A Th1 response is usually associated with infection control, while a predominant Th2 response is detrimental to the patient. In this scenario, the enzymes arginase and inducible nitric oxide synthase represent two possible pathways of immune response. While the former contributes to parasite replication, the latter is crucial for its control. In the present review, we collected study results that associate arginase expression in patients and in experimental models with disease susceptibility/chronicity and show some proposed mechanisms that explain the role of arginase in maintaining Leishmania infection, including polyamine and thiol synthesis, tissue-resident macrophage (TRM) proliferation and activation and T-cell suppression and exhaustion.


Assuntos
Arginase/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Inata/imunologia , Leishmaniose/parasitologia , Neutrófilos/imunologia , Células Th1/imunologia , Células Th2/imunologia
9.
Trends Parasitol ; 36(5): 459-472, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32298633

RESUMO

Inflammasomes are cytosolic complexes that assemble in response to cellular stress or upon sensing microbial molecules, culminating in cytokine processing and an inflammatory form of cell death called pyroptosis. Inflammasomes are usually composed of a sensor molecule, an adaptor protein, and an inflammatory caspase, such as Caspase-1, which cleaves and activates multiple substrates, including Gasdermin-D, pro-IL-1ß, and pro-IL-18. Ultimately, inflammasome activation promotes inflammation and restriction of the microbial infection. In recent years, many studies have addressed the role of inflammasomes during fungal, bacterial, viral, and parasitic diseases, revealing sophisticated aspects of the host-pathogen interaction. In this review, we summarize recent advances on inflammasome activation in response to intracellular parasites, including Leishmania spp., Plasmodium spp., Trypanosoma cruzi, and Toxoplasma gondii.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/imunologia , Infecções por Protozoários/imunologia , Animais , Eucariotos/imunologia , Humanos , Leishmaniose/imunologia , Leishmaniose/parasitologia , Malária/imunologia , Malária/parasitologia , Infecções por Protozoários/parasitologia , Pesquisa/tendências , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Tripanossomíase/imunologia , Tripanossomíase/parasitologia
10.
Parasit Vectors ; 13(1): 181, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32268916

RESUMO

BACKGROUND: Leishmaniasis is a human and animal disease caused by parasites of the genus Leishmania, which is now divided into four subgenera, Leishmania, Viannia, Sauroleishmania and Mundinia. Subgenus Mundinia, established in 2016, is geographically widely dispersed, its distribution covers all continents, except Antarctica. It consists of 5 species; L. enriettii and L. macropodum are parasites of wild mammals while L. martiniquensis, L. orientalis and an unnamed Leishmania sp. from Ghana are infectious to humans. There is very little information on natural reservoir hosts and vectors for any Mundinia species. METHODS: Experimental infections of guinea pigs with all five Mundinia species were performed. Animals were injected intradermally with 107 culture-derived promastigotes into both ear pinnae. The courses of infections were monitored weekly; xenodiagnoses were performed at weeks 4 and 8 post-infection using Lutzomyia migonei. The distribution of parasites in different tissues was determined post-mortem by conventional PCR. RESULTS: No significant differences in weight were observed between infected animals and the control group. Animals infected with L. enriettii developed temporary lesions at the site of inoculation and were infectious to Lu. migonei in xenodiagnoses. Animals infected with L. martiniquensis and L. orientalis developed temporary erythema and dry lesions at the site of inoculation, respectively, but were not infectious to sand flies. Guinea pigs infected by L. macropodum and Leishmania sp. from Ghana showed no signs of infection during experiments, were not infectious to sand flies and leishmanial DNA was not detected in their tissue samples at the end of experiments at week 12 post-inoculation. CONCLUSIONS: According to our results, guinea pigs are not an appropriate model organism for studying Mundinia species other than L. enriettii. We suggest that for better understanding of L. (Mundinia) biology it is necessary to focus on other model organisms.


Assuntos
Modelos Animais de Doenças , Leishmania/crescimento & desenvolvimento , Leishmaniose/veterinária , Animais , Feminino , Cobaias , Leishmania/classificação , Leishmaniose/parasitologia
11.
Carbohydr Polym ; 237: 116120, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32241437

RESUMO

Leishmania is an obligate intracellular pathogen that invades phagocytic host cells. Due to its high morbidity and mortality rates, leishmaniasis attracts significant attention. The disease, which is caused by Leishmania parasites, is distributed worldwide, particularly among developing communities, and causes fatal complications if not treated expediently. Unfortunately, the existing treatments are not preventive and do not impede Leishmania infection. Many drugs available for leishmaniasis are becoming less effective due to emerging resistance in some Leishmania species. Other drugs have drawbacks such as low cost-effectiveness, toxicity, and side effects. The World Health Organization (WHO) considers leishmaniasis to be a major public health problem and suggests that the best prevention is to develop a vaccine for this dangerous disease. In this review, we focus on the unique components of lipophosphoglycan (LPG), a component of the Leishmania cell wall, particularly [Galp(1 → 4)-ß-[Manp-(1 → 2)-α-Manp-(1 → 2)-α]-Manp] in the cryptic tetrasaccharide cap, and on synthetic approaches as a potent candidate for a leishmaniasis vaccine.


Assuntos
Glicoproteínas/química , Glicoesfingolipídeos/química , Leishmania/química , Leishmaniose/parasitologia , Humanos , Leishmaniose/prevenção & controle , Vacinas contra Leishmaniose
12.
Am J Trop Med Hyg ; 102(6): 1323-1327, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228793

RESUMO

Multiple polymerase chain reaction (PCR)-based approaches have been developed for Leishmania detection in clinical and laboratory samples, and this diversity limits inter-study comparisons, meta-analyses, and generalization of findings. Towards harmonization of a molecular tool for detection of Leishmania (Viannia) for research purposes, we evaluated the concordance of 18SrDNA quantitative polymerase chain reaction (qPCR) and minicircle kinetoplastid DNA (mkDNA) PCR followed by Southern blot (PCR-SB) in in vitro infection systems and in lesion and mucosal swab samples from Colombian patients with cutaneous leishmaniasis caused by L. (Viannia). The lower limit of parasite detection of 18SrDNA qPCR and mkDNA PCR-SB was 10-1 promastigotes and one intracellular amastigote per reaction. From cutaneous lesions (n = 63), an almost perfect concordance was found between the methods (κ = 0.92, 95% CI: 0.82-1.00). Despite equal limits of detection, mkDNA PCR-SB was more efficient for parasite detection in mucosal samples than 18SrDNA qPCR or 18SrDNA digital droplet PCR. The high concordance, sensitivity, scaling potential, and feasibility of implementation of the 18SrDNA qPCR, support its selection as the L. (Viannia) in research laboratories, as a first step towards harmonization of research protocols in the region.


Assuntos
DNA de Protozoário/genética , Leishmania/isolamento & purificação , Leishmaniose/diagnóstico , Leishmaniose/parasitologia , Técnicas de Amplificação de Ácido Nucleico , Linhagem Celular , Túnica Conjuntiva/parasitologia , Feminino , Humanos , Limite de Detecção , Masculino , Monócitos/parasitologia , Mucosa Nasal/parasitologia , Tonsila Palatina/parasitologia , Especificidade da Espécie
13.
Int J Mol Sci ; 21(5)2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32121441

RESUMO

Unicellular eukaryotes of the Trypanosomatidae family include human and animal pathogens that belong to the Trypanosoma and Leishmania genera. Diagnosis of the diseases they cause requires the sampling of body fluids (e.g., blood, lymph, peritoneal fluid, cerebrospinal fluid) or organ biopsies (e.g., bone marrow, spleen), which are mostly obtained through invasive methods. Body fluids or appendages can be alternatives to these invasive biopsies but appropriateness remains poorly studied. To further address this question, we perform a systematic review on clues evidencing the presence of parasites, genetic material, antibodies, and antigens in body secretions, appendages, or the organs or proximal tissues that produce these materials. Paper selection was based on searches in PubMed, Web of Science, WorldWideScience, SciELO, Embase, and Google. The information of each selected article (n = 333) was classified into different sections and data were extracted from 77 papers. The presence of Trypanosomatidae parasites has been tracked in most of organs or proximal tissues that produce body secretions or appendages, in naturally or experimentally infected hosts. The meta-analysis highlights the paucity of studies on human African trypanosomiasis and an absence on animal trypanosomiasis. Among the collected data high heterogeneity in terms of the I2 statistic (100%) is recorded. A high positivity is recorded for antibody and genetic material detection in urine of patients and dogs suffering leishmaniasis, and of antigens for leishmaniasis and Chagas disease. Data on conjunctival swabs can be analyzed with molecular methods solely for dogs suffering canine visceral leishmaniasis. Saliva and hair/bristles showed a pretty good positivity that support their potential to be used for leishmaniasis diagnosis. In conclusion, our study pinpoints significant gaps that need to be filled in order to properly address the interest of body secretion and hair or bristles for the diagnosis of infections caused by Leishmania and by other Trypanosomatidae parasites.


Assuntos
Leishmania/isolamento & purificação , Trypanosoma/isolamento & purificação , Trypanosomatina/isolamento & purificação , Animais , Doença de Chagas/diagnóstico , Doença de Chagas/parasitologia , Doenças do Cão/diagnóstico , Doenças do Cão/parasitologia , Cães , Humanos , Leishmania/patogenicidade , Leishmaniose/diagnóstico , Leishmaniose/parasitologia , Trypanosoma/patogenicidade , Trypanosomatina/patogenicidade , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/veterinária
14.
Acta Trop ; 207: 105456, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32222362

RESUMO

Leishmania are obligate intracellular parasites of mononuclear phagocytes transmitted by Phlebotomine sandflies. Monocytes are one of the main cell types recruited to the site of the bite having an important role in the defense against Leishmania parasites in the first hours of infection. In the tissue, macrophages play a pivotal role as both the primary replication sites and the major effector cells responsible for parasite elimination. Many authors have reviewed the monocyte/macrophage-Leishmania interactions from results derived in mice, however, given the important differences between mice an humans we considered vital to discuss the role of these cells in human leishmaniasis. In this review, we recapitulated the most important studies carried out to understand the different roles of human monocyte/macrophages in Leishmania infection and how they can participate in both control and the immunopathogenesis of the disease.


Assuntos
Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/fisiologia , Monócitos/fisiologia , Óxido Nítrico/metabolismo , Animais , Humanos , Leishmaniose/parasitologia , Camundongos , Espécies Reativas de Oxigênio
15.
Hum Genet ; 139(6-7): 813-819, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32055998

RESUMO

Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (Pcombined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P < 5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.


Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Genética Humana , Leishmania/imunologia , Leishmaniose/genética , Leishmaniose/imunologia , Polimorfismo de Nucleotídeo Único , Regulação da Expressão Gênica , Antígenos HLA/imunologia , Humanos , Leishmania/genética , Leishmaniose/parasitologia
16.
Pathog Dis ; 78(1)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32053190

RESUMO

Leishmaniasis includes a broad spectrum of pathological outcomes in humans caused by protozoan parasites from the genus Leishmania. In recent years, proteomic techniques have introduced novel proteins with critical functions in Leishmania parasites. Based on our report of a Chitin binding protein (CBP) in our previous immunoproteomic study, this article suggests that CBP might be an RNA binding protein (RBP) in Leishmania parasites. RBPs, as key regulatory factors, have a role in post-transcriptional gene regulation. The presence of RBPs in Leishmania parasites has not been considered so far; however, this study aims to open a new venue regarding RBPs in Leishmania parasites. Confirming CBP as an RBP in Leishmania parasites, exploring other RBPs and their functions might lead to interesting issues in leishmaniasis. In fact, due to the regulatory role of RBPs in different diseases including cancers and their further classification as therapeutic targets, the emerging evaluation of CBP and RBPs from Leishmania parasites may allow the discovery of novel and effective drugs against leishmaniasis.


Assuntos
Proteínas de Transporte/metabolismo , Quitina/metabolismo , Leishmania/metabolismo , Proteínas de Ligação a RNA/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmaniose/parasitologia , Ligação Proteica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
17.
Trends Parasitol ; 36(3): 279-289, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32005611

RESUMO

Species of the protozoan Leishmania are causative agents of human leishmaniasis, a disease that results in significant death, disability, and disfigurement around the world. The parasite is transmitted to a mammalian host by a sand fly vector where it develops as an intracellular parasite within macrophages. This process requires the acquisition of nutritional iron and heme from the host as Leishmania lacks the capacity for de novo heme synthesis and does not contain cytosolic iron-storage proteins. Proteins involved in Leishmania iron and heme transport and metabolism have been identified and shown to be crucial for the parasite's growth and replication within the host. Consequently, a detailed understanding of how these parasites harness host pathways for survival may lay the foundation for promising new therapeutic intervention against leishmaniasis.


Assuntos
Heme/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Ferro/metabolismo , Leishmania/metabolismo , Leishmaniose/parasitologia , Animais , Humanos
18.
PLoS Negl Trop Dis ; 14(2): e0007983, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32106219

RESUMO

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS.


Assuntos
Alanina-tRNA Ligase/antagonistas & inibidores , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Treonina-tRNA Ligase/antagonistas & inibidores , Trypanosoma/efeitos dos fármacos , Alanina-tRNA Ligase/genética , Alanina-tRNA Ligase/metabolismo , Antiprotozoários/química , Inibidores Enzimáticos/química , Humanos , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmaniose/parasitologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Treonina-tRNA Ligase/genética , Treonina-tRNA Ligase/metabolismo , Trypanosoma/enzimologia , Trypanosoma/genética , Tripanossomíase/parasitologia
19.
PLoS Negl Trop Dis ; 14(1): e0007949, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961876

RESUMO

Leishmaniasis is caused by intracellular parasites transmitted to vertebrates by sandfly bites. Clinical manifestations include cutaneous, mucosal or visceral involvement depending upon the host immune response and the parasite species. To assure their survival inside macrophages, these parasites developed a plethora of highly successful strategies to manipulate various immune system pathways. Considering that inflammasome activation is critical for the establishment of a protective immune response in many parasite infections, in this study we determined the transcriptome of THP-1 cells after infection with L. infantum, with a particular focus on the inflammasome components. To this end, the human cell line THP-1, previously differentiated into macrophages by PMA treatment, was infected with L. infantum promastigotes. Differentiated THP-1 cells were also stimulated with LPS to be used as a comparative parameter. The gene expression signature was determined 8 hours after by RNA-seq technique. Infected or uninfected THP-1 cells were stimulated with nigericin (NIG) to measure active caspase-1 and TNF-α, IL-6 and IL-1ß levels in culture supernatants after 8, 24 and 48 hours. L. infantum triggered a gene expression pattern more similar to non-infected THP-1 cells and very distinct from LPS-stimulated cells. Some of the most up-regulated genes in L. infantum-infected cells were CDC20, CSF1, RPS6KA1, CD36, DUSP2, DUSP5, DUSP7 and TNFAIP3. Some up-regulated GO terms in infected cells included cell coagulation, regulation of MAPK cascade, response to peptide hormone stimulus, negative regulation of transcription from RNA polymerase II promoter and nerve growth factor receptor signaling pathway. Infection was not able to induce the expression of genes associated with the inflammasome signaling pathway. This finding was confirmed by the absence of caspase-1 activation and IL-1ß production after 8, 24 and 48 hours of infection. Our results indicate that L. infantum was unable to activate the inflammasomes during the initial interaction with THP-1 cells.


Assuntos
Inflamassomos/imunologia , Leishmania infantum/fisiologia , Leishmaniose/genética , Monócitos/imunologia , Monócitos/parasitologia , Caspase 1/genética , Caspase 1/imunologia , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/imunologia , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Células THP-1 , Transcriptoma , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
20.
Molecules ; 25(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979089

RESUMO

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Tetraoxanos/química , Tetraoxanos/uso terapêutico , Animais , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/uso terapêutico
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