scholarly journals Inhibition of ABC Transporters Abolishes Antimony Resistance in Leishmania Infection

2007 ◽  
Vol 52 (3) ◽  
pp. 1080-1093 ◽  
Author(s):  
Jayati Mookerjee Basu ◽  
Ananda Mookerjee ◽  
Rajdeep Banerjee ◽  
Manik Saha ◽  
Subhankar Singh ◽  
...  
Keyword(s):  
Abc Transporters ◽  
Leishmania Donovani ◽  
Host Cells ◽  
Leishmania Infection ◽  
Blood Monocytes ◽  
Glycoprotein P ◽  
Kala Azar ◽  
Antimony Resistance ◽  
Parasite Replication

ABSTRACT The emergence of antimony (Sb) resistance has jeopardized the treatment of visceral leishmaniasis in various countries. Previous studies have considered the part played by leishmanial parasites in antimony resistance, but the involvement of host factors in the clinical scenario remained to be investigated. Here we show that unlike infection with Sb-sensitive (Sbs) Leishmania donovani, infection with Sb-resistant (Sbr) L. donovani induces the upregulation of multidrug resistance-associated protein 1 (MRP1) and permeability glycoprotein (P-gp) in host cells, resulting in a nonaccumulation of intracellular Sb following treatment with sodium antimony gluconate (SAG) favoring parasite replication. The inhibition of MRP1 and P-gp with resistance-modifying agents such as lovastatin allows Sb accumulation and parasite killing within macrophages and offers protection in an animal model in which infection with Sbr L. donovani is otherwise lethal. The occurrence of a similar scenario in clinical cases is supported by the findings that unlike monocytes from SAG-sensitive kala-azar (KA) patients, monocytes from SAG-unresponsive KA patients overexpress P-gp and MRP1 and fail to accumulate Sb following in vitro SAG treatment unless pretreated with inhibitors of ABC transporters. Thus, the expression status of MRP1 and P-gp in blood monocytes may be used as a diagnostic marker for Sb resistance and the treatment strategy can be designed accordingly. Our results also indicate that lovastatin, which can inhibit both P-gp and MRP1, might be beneficial for reverting Sb resistance in leishmaniasis as well as drug resistance in other clinical situations, including cancer.

scholarly journals In Vitro and In Vivo Activities of a Triterpenoid Saponin Extract (PX-6518) from the Plant Maesa balansae against Visceral Leishmania Species

2004 ◽  
Vol 48 (1) ◽  
pp. 130-136 ◽  
Author(s):  
Louis Maes ◽  
Dirk Vanden Berghe ◽  
Nils Germonprez ◽  
Ludo Quirijnen ◽  
Paul Cos ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Human Fibroblasts ◽  
Subcutaneous Administration ◽  
Leishmania Species ◽  
Host Cells ◽  
Triterpenoid Saponin ◽  
Sodium Stibogluconate ◽  
Triterpenoid Saponins

ABSTRACT The in vitro and in vivo activities of a mixture of six oleane triterpene saponins, recovered from the methanolic extract of the leaves of the Vietnamese plant Maesa balansae (PX-6518), were evaluated against drug-sensitive visceral Leishmania strains. The in vitro 50% inhibitory concentration (IC50) against intracellular Leishmania infantum amastigotes was 0.04 μg/ml. The cytotoxic concentrations causing 50% cell death (CC50s) were about 1 μg/ml in murine macrophage host cells and >32 μg/ml in human fibroblasts (MRC-5 cell line). Evaluation in the Leishmania donovani BALB/c mouse model indicated that a single subcutaneous administration of 0.4 mg/kg at 1 day after infection reduced liver amastigote burdens by about 95% in all treated animals. If treatment was delayed until 14 days after infection, a dose of 1.6 mg/kg of body weight was required to maintain the same level of activity. Single 250-mg/kg doses of sodium stibogluconate (Pentostam) 1 and 14 days after infection produced comparable efficacies. A single dose of PX-6518 at 2.5 mg/kg administered 5 days before infection was still 100% effective in preventing liver infection, suggesting a particularly long residual action. Spleen and bone marrow could not be cleared by PX-6518 nor sodium stibogluconate. PX-6518 did not show activity after oral dosing at up to 200 mg/kg for 5 days. This study concludes that triterpenoid saponins from M. balansae show promising in vitro and in vivo antileishmanial potential and can be considered as new lead structures in the search for novel antileishmanial drugs.

scholarly journals Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Arun Kumar Haldar ◽  
Pradip Sen ◽  
Syamal Roy
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Current Status ◽  
Vanadium Compounds ◽  
Future Directions ◽  
Kala Azar ◽  
Efflux Mechanism ◽  
Transplantation Antigens ◽  
Antigen Presenting

In the recent past the standard treatment of kala-azar involved the use of pentavalent antimonials Sb(V). Because of progressive rise in treatment failure to Sb(V) was limited its use in the treatment program in the Indian subcontinent. Until now the mechanism of action of Sb(V) is not very clear. Recent studies indicated that both parasite and hosts contribute to the antimony efflux mechanism. Interestingly, antimonials show strong immunostimulatory abilities as evident from the upregulation of transplantation antigens and enhanced T cell stimulating ability of normal antigen presenting cells when treated with Sb(V) in vitro. Recently, it has been shown that some of the peroxovanadium compounds have Sb(V)-resistance modifying ability in experimental infection with Sb(V) resistant Leishmania donovani isolates in murine model. Thus, vanadium compounds may be used in combination with Sb(V) in the treatment of Sb(V) resistance cases of kala-azar.

scholarly journals Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

2018 ◽  
Vol 45 (2) ◽  
pp. 591-604 ◽  
Author(s):  
Guinever Eustaquio do Imperio ◽  
Enrrico Bloise ◽  
Mohsen Javam ◽  
Phetcharawan Lye ◽  
Andrea Constantinof ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Staining Intensity ◽  
Distinct Pattern ◽  
Mrna Levels ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Immunological Responses

Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

scholarly journals INVESTIGATION OF LEISHMANIASIS VECTORS IN EL-KADOBA VILLAGE, WHITE NILE STATE, SUDAN

2017 ◽  
Vol 5 (1) ◽  
pp. 430-441
Author(s):  
Belal Abdallah A. Adam ◽  
Moawia Mukhtar Hassan ◽  
Osman Mohammed Abd Elnour ◽  
Ahmed Hamid Awadallah
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Morphological Characters ◽  
Sand Fly ◽  
Leishmania Infection ◽  
Sand Flies ◽  
Kala Azar ◽  
Ecological Aspects ◽  
Binocular Microscope ◽  
White Nile

Visceral leishmaniasis (VL; kala-azar) is one of the most important parasitic tropical diseases in Sudan   and the Sudan is considered to be one of the most important foci in the world. The visceral leishmaniasis has been described in Sudan since the beginning of the twentieth century. In Sudan, VL is caused by Leishmania donovani complex: MON 18, MON 30 and MON 82 zymodemes and  The proven vector is Phlebotomus (Larroussius) orientalis, in this study a survey was carried out to identify the principal vector of VL based on Leishmania infection, morphological characters and to determine some ecological aspects of the sand flies prevalent in the area . Ten species of sand flies were recorded, three Phlebotomus species and seven Sergentomyia species of these sandflies, P. rodhaini was collected only from Acacia seyal/Balanities aegyptiaca at the Island whereas S. hunti was collected from the Acacia nilotica forest only of the total collections, P. orientalis representing 3.80% (248 specimens) of the total collection and P. papatasi were 3.11% of the collection. Sand flies identification was done under a binocular microscope at 40x (magnification). The main features used for sand flies identification were the sperm theca of the female, the termination of the male and the pharyngeal and the ciboria toothed structures of both sexes. According to results of this study we recommended the following:  more studies are needed in the future to determine the transmission season, and infection rates of Leishmania parasites in human and the animal host in this area. Annually Entomological surveys must be done to determine density of Sand fly Vectors and Encourage the use of personal protection tools (ITNs), repellents, and improving of houses to avoid bite of sand fly.

scholarly journals Involvement of ABC-transporters and acyltransferase 1 in intracellular cholesterol-mediated autophagy in bovine alveolar macrophages in response to the Bacillus Calmette-Guerin (BCG) infection

2020 ◽  
Author(s):  
Jinrui Xu ◽  
Yanbing Zhou ◽  
Yi Yang ◽  
Cuiping Lv ◽  
Xiaoming Liu ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Abc Transporters ◽  
Alveolar Macrophages ◽  
Cholesterol Metabolism ◽  
Present Report ◽  
Host Cells ◽  
Bacillus Calmette Guerin ◽  
Public Health Burden ◽  
Intracellular Cholesterol

Abstract Background: Understanding pathogenic mechanisms is imperative for developing novel treatment to the tuberculosis, an important public health burden worldwide. Recent studies demonstrated that host cholesterol levels have implications in the establishment of Mycobacterium tuberculosis ( M. tuberculosis , Mtb ) i nfection in host cells, in which the intracellular cholesterol-mediated ATP-binding cassette transporters (ABC-transporters) and cholesterol acyltransferase1 (ACAT1) exhibited abilities to regulate macrophage autophagy induced by Mycobacterium bovis Bacillus Calmette–Guérin (BCG). Methods: In the present report, the involvements of ABC-transporters and ACAT1-mediated intracellular cholesterol in autophagy of bovine alveolar macrophages induced by Mycobacterium bovis BCG were interrogated by enzymatic and biochemistry assays in vitro, including quantitative RT-PCR and immunoblotting assays. Results: The results showed that a down-regulated expression of the ABC-transporters and ACAT1 in primary bovine alveolar macrophages (AMs) and murine RAW264.7 cells in response to BCG infection. The inhibited expression of ABC-transporters and ACAT1 was associated with the reduction of intracellular free cholesterol, which in turn induced autophagy in macrophages upon to the Mycobacterial infection. These results strongly suggest an involvement of ABC-transporters and ACAT1 in intracellular cholesterol-mediated autophagy in AMs in response to BCG infection. Conclusion: This study thus provides an insight into into a mechanism by which the cholesterol metabolism regulated the autophagy in macrophages in response to mycobacterial infections .

scholarly journals Involvement of ABC-transporters and acyltransferase 1 in intracellular cholesterol-mediated autophagy in bovine alveolar macrophages in response to the Bacillus Calmette-Guerin (BCG) infection

2020 ◽  
Author(s):  
Jinrui Xu ◽  
Yanbing Zhou ◽  
Yi Yang ◽  
Cuiping Lv ◽  
Xiaoming Liu ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Abc Transporters ◽  
Alveolar Macrophages ◽  
Cholesterol Metabolism ◽  
Present Report ◽  
Host Cells ◽  
Bacillus Calmette Guerin ◽  
Public Health Burden ◽  
Intracellular Cholesterol

Abstract Background: Understanding pathogenic mechanisms is imperative for developing novel treatment to the tuberculosis, an important public health burden worldwide. Recent studies demonstrated that host cholesterol levels have implications in the establishment of Mycobacterium tuberculosis ( M. tuberculosis , Mtb ) i nfection in host cells, in which the intracellular cholesterol-mediated ATP-binding cassette transporters (ABC-transporters) and cholesterol acyltransferase1 (ACAT1) exhibited abilities to regulate macrophage autophagy induced by Mycobacterium bovis Bacillus Calmette–Guérin (BCG). Methods: In the present report, the involvements of ABC-transporters and ACAT1-mediated intracellular cholesterol in autophagy of bovine alveolar macrophages induced by Mycobacterium bovis BCG were interrogated by enzymatic and biochemistry assays in vitro, including quantitative RT-PCR and immunoblotting assays. Results: The results showed that a down-regulated expression of the ABC-transporters and ACAT1 in primary bovine alveolar macrophages (AMs) and murine RAW264.7 cells in response to BCG infection. The inhibited expression of ABC-transporters and ACAT1 was associated with the reduction of intracellular free cholesterol, which in turn induced autophagy in macrophages upon to the Mycobacterial infection. These results strongly suggest an involvement of ABC-transporters and ACAT1 in intracellular cholesterol-mediated autophagy in AMs in response to BCG infection. Conclusion: This study thus provides an insight into into a mechanism by which the cholesterol metabolism regulated the autophagy in macrophages in response to mycobacterial infections .

scholarly journals Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Markela Koniordou ◽  
Stephen Patterson ◽  
Susan Wyllie ◽  
Karin Seifert
Keyword(s):  
Host Cell ◽  
Leishmania Donovani ◽  
Host Cells ◽  
Content Type ◽  
Human Macrophages ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Intracellular Amastigotes ◽  
Peritoneal Exudate Macrophages

ABSTRACT This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.

scholarly journals Different innate immunity and clearance of Salmonella Pullorum in macrophages from White Leghorn and Tibetan Chickens

2018 ◽  
Vol 16 ◽  
pp. 205873921878003 ◽  
Author(s):  
Shao Wei ◽  
Keliang Wu ◽  
Yijuan Nie ◽  
Xiang Li ◽  
Zhengxing Lian ◽  
...  
Keyword(s):  
Immune Response ◽  
Interleukin 10 ◽  
Host Cells ◽  
Blood Monocytes ◽  
White Leghorn ◽  
Inflammatory Protein ◽  
Crucial Effect ◽  
Salmonella Pullorum ◽  
Macrophage Inflammatory Protein

Salmonella enterica serovar Gallinarum biovar Pullorum ( S. Pullorum) is responsible for the systemic salmonellosis in different breeds of chickens. Macrophages, as host cells, play a key role in the innate immune response following infection with S. Pullorum. In this study, we first generated macrophages from two breeds of chicken (White Leghorn (WL) and Tibetan Chickens (TC)) peripheral blood monocytes in vitro. Then, we showed that the production of interleukin-1β (IL-1β), macrophage inflammatory protein-1β (MIP-1β) and interleukin-10 (IL-10) in lipopolysaccharide (LPS)-treated macrophages was significantly higher compared with the unstimulated cells in TC. LPS triggered only more expression of IL-10 in WL macrophages. Furthermore, macrophages from TC eliminated intracellular bacteria more efficiently than those from WL after S. Pullorum infection at a multiplicity of infection (MOI) 1. In addition, the variation between individuals and sex had the crucial effect on the immune response to LPS and S. Pullorum invasion.

scholarly journals Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

Pathogens ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 393
Author(s):  
Kyung-Hwa Baek ◽  
Laura Piel ◽  
Thibault Rosazza ◽  
Eric Prina ◽  
Gerald F. Späth ◽  
...  
Keyword(s):  
Host Cell ◽  
Leishmania Donovani ◽  
Early Stage ◽  
Drug Susceptibility ◽  
Host Cells ◽  
Acute Monocytic Leukemia ◽  
Cell Infection ◽  
Monocytic Leukemia ◽  
Vitro Assay

Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a spectrum of a disease that threatens public health worldwide. Although next-generation therapeutics are urgently needed, the early stage of the drug discovery process is hampered by very low hit rates from intracellular Leishmania phenotypic high-throughput screenings. Designing and applying a physiologically relevant in vitro assay is therefore in high demand. In this study, we characterized the infectivity, morphology, and drug susceptibility of different Leishmania and host cell infection combinations. Primary bone marrow-derived macrophage (BMDM) and differentiated human acute monocytic leukemia (THP-1) cells were infected with amastigote or promastigote forms of Leishmania amazonensis and Leishmania donovani. Regardless of host cell types, amastigotes were generally well phagocytosed and showed high infectivity, whereas promastigotes, especially those of L. donovani, had predominantly remained in the extracellular space. In the drug susceptibility test, miltefosine and sodium stibogluconate (SSG) showed varying ranges of activity with 14 and >10-fold differences in susceptibility, depending on the host-parasite pairs, indicating the importance of assay conditions for evaluating antileishmanial activity. Overall, our results suggest that combinations of Leishmania species, infection forms, and host cells must be carefully optimized to evaluate the activity of potential therapeutic compounds against Leishmania.

scholarly journals A Novel Strategy for Enhance Potentiation of Meglumine antimo-niate against Leishmania major In Vitro

2019 ◽  
Author(s):  
Farzaneh MIRZAEI ◽  
Hossein KHANAHMAD ◽  
Fatemeh NAMDAR ◽  
Shahrokh IZADI ◽  
Seyed Hossein HEJAZI
Keyword(s):  
Leishmania Major ◽  
Host Cells ◽  
Leishmania Infection ◽  
Listeriolysin O ◽  
Meglumine Antimoniate ◽  
Dose Concentration ◽  
Vitro Model ◽  
Novel Strategy ◽  
Hlya Gene

Background: We aimed to design a different method of drug delivery for increased transfer of the choice drug (meglumine antimoniate) within the host cells. Therefore, listeriolysin O (LLO), a bacterial product which is a member of pore-forming peptides was used as an enhancer factor with meglumine antimoniate in order to facilitate the transition of the drug across macrophage membrane. Methods: LLO was produced in Isfahan University of Medical Sciences in 2016, by expressing the hlyA gene in Escherichia coli and purified using affinity chromatography. Cytotoxicity of the purified protein was investigated in an in vitro model of macrophage Leishmania infection. Results: LLO was cytotoxic against murine macrophage cells (J774-A1) and amastigote forms of L. major (MRHO/IR/75/ER). It was less toxic to macrophages (CC50=2.56 μg ml-1 ±0.09) than to the parasites (IC50=1.72 μg ml-1 ±0.07). Moreover, non-cytotoxic concentration of LLO (0.006 ug ml-1) potentiated the cytotoxicity induced by low dose concentration of meglumine antimoniate. Very little dose of meglumine antimoniate was needed when combined with the LLO (IC50=12.63 μg ml-1 ±0.13) in comparison with the cytotoxicity induced when the drug is used alone (IC50=46.17 μg ml-1 ±0.28). Conclusion: The combination of pore-forming proteins with anti-leishmanial agents could increase the advantage of anti-leishmanial drugs. Since lower concentrations of anti-leishmanial drugs can reduce undesirable side effects of chemotherapy trials carried out in animal models and then in humans with this system.

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