Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence Fungal and Parasitic Infections

The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H2O2 is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H2O2. Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H2O2, generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoc...
Source: Infection and Immunity - Category: Infectious Diseases Authors: Tags: Fungal and Parasitic Infections Source Type: research

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ConclusionWith regard to the supportive role of bax in apoptosis and the preventive role of Leishmania in its function, it seems that expression of bax gene in parasite by technologies like transgenic or down regulating of anti-apoptotic molecule Bcl-2 by miRNA could be prompted the apoptosis process of infected-macrophages and inhibited extensive spread of Leishmania and the resulting lesions.
Source: Microbial Pathogenesis - Category: Infectious Diseases Source Type: research
Abstract Leishmaniasis, caused by the intracellular protozoan parasite Leishmania, remains an important neglected tropical infectious disease. Infection may be lethal if untreated. Currently, the available drugs for the disease are limited by high toxicity and drug resistance. There is an urgent need to develop novel anti-leishmanial strategies. Antimicrobial peptides (AMPs) have been described as the first-line immune defense against pathogenic microbes and are being developed as emerging anti-parasitic therapies. In the present study, we showed the anti-leishmanial activity of the synthetic 4-amino acid peptide ...
Source: Acta Biochimica et Biophysica Sinica - Category: Biochemistry Authors: Tags: Acta Biochim Biophys Sin (Shanghai) Source Type: research
Publication date: Available online 15 November 2019Source: Chemico-Biological InteractionsAuthor(s): Paula Roberta da Silva, Jamerson Ferreira de Oliveira, Anekécia Lauro da Silva, Camila Marques Queiroz, Ana Paula Sampaio Feitosa, Denise Maria Figueiredo Araújo Duarte, Aline Caroline da Silva, Maria Carolina Accioly Brelaz de Castro, Valéria Rêgo Alves Pereira, Rosali Maria Ferreira da Silva, Luiz Carlos Alves, Fábio André Brayner dos Santos, Maria do Carmo Alves de LimaAbstractParasitic diseases still represent serious public health problems, since the high and steady emergence of...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research
In conclusion, the L. infantum death may be ascribed by the subcellular alterations followed by a pronounced decrease in the mitochondrial membrane potential, indicating dysfunction in the respiratory chain upon H1-antihistamine treatment. These H1-antihistamines could be used to explore new routes of cellular death in the parasite and the determination of the targets at a molecular level, would contribute to understanding the potential of these drugs as antileishmanial. PMID: 31002807 [PubMed - as supplied by publisher]
Source: Acta Tropica - Category: Infectious Diseases Authors: Tags: Acta Trop Source Type: research
In this study we found blocking autophagy led to increased CP growth in both macrophages and mouse embryonic fibroblasts. In vivo, loss of the autophagy elongation component ATG16L1 specifically in myeloid cells led to increased mortality in response to CP infection, characterized by greater numbers of neutrophils and dendritic cells, but no change in the CP burden in the lungs. This was accompanied by an increase in inflammasome-active macrophages and IL-1β production. While induction of autophagy in macrophages led to reduced CP growth in vitro, in vivo treatment with rapamycin led to increased mortality of infected...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
avanelli WR Abstract Leishmania parasites infect macrophages causing a wide spectrum of human diseases encompassing from cutaneous to visceral forms. The drugs currently used in leishmaniasis treatment are highly toxic and associated with acquired resistance. Seeking novel therapeutic targets, we conducted a comprehensive in vitro study to investigate the action of trans-chalcone (TC) against Leishmania amazonensis promastigote and amastigote forms. TC is a common precursor of flavonoids, however, no extensive research has been developed regarding its pharmacological properties. In silico predictions showed good d...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research
Publication date: Available online 29 March 2019Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): Rubén Martín-Escolano, Rubén Cebrián, Javier Martín-Escolano, Maria J. Rosales, Mercedes Maqueda, Manuel Sánchez-Moreno, Clotilde MarínAbstractChagas disease caused by the protozoan parasite Trypanosoma cruzi represents a significant public health problem in Latin America, affecting around 8 million cases worldwide. Nowadays is urgent the identification of new antichagasic agents as the only therapeutic options available, Nifurtimox and Benznida...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research
Abstract The choice of cost-effective molecular methods for diagnosing and monitoring of Chagas disease before and after treatment is crucial in endemic countries with high patients' demand and limited financial resources. To this end, a kDNA was compared to a satellite real-time quantitative PCR (sat-qPCR), both amplifications using Sybr Green instead of Taqman hydrolysis probes. Non-isogenic Swiss albino mice were infected with a small inoculum of the highly virulent and partially resistant to benznidazole Y strain, belonging to T. cruzi discrete typing unit II (DTU-II) that predominates in Atlantic and Central ...
Source: Experimental Parasitology - Category: Parasitology Authors: Tags: Exp Parasitol Source Type: research
In conclusion, the NP studied can be used for incorporating potent leishmanicidal chemotherapy, due to their selectivity towards macrophages, being a promising system for the treatment of cutaneous leishmaniasis. PMID: 30659806 [PubMed - as supplied by publisher]
Source: Acta Tropica - Category: Infectious Diseases Authors: Tags: Acta Trop Source Type: research
Conclusion: CA showed in vitro antipromastigote and antiamostigote by increasing oxidant and inflammatory response important to eliminate the parasite.Graphical abstractW
Source: Phytomedicine - Category: Drugs & Pharmacology Source Type: research
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