scholarly journals Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection with L. amazonensis

2021 ◽  
Vol 22 (13) ◽  
pp. 6883
Author(s):  
Maricruz Mamani-Huanca ◽  
Sandra Marcia Muxel ◽  
Stephanie Maia Acuña ◽  
Lucile Maria Floeter-Winter ◽  
Coral Barbas ◽  
...  
Keyword(s):  
Metabolic Networks ◽  
Urea Cycle ◽  
Host Cells ◽  
Leishmania Infection ◽  
Glutathione Metabolism ◽  
No Production ◽  
Parasite Relationship ◽  
Infectivity Rate ◽  
Serine Metabolism ◽  
Metabolite Abundance

Leishmania survival inside macrophages depends on factors that lead to the immune response evasion during the infection. In this context, the metabolic scenario of the host cell–parasite relationship can be crucial to understanding how this parasite can survive inside host cells due to the host’s metabolic pathways reprogramming. In this work, we aimed to analyze metabolic networks of bone marrow-derived macrophages from C57BL/6 mice infected with Leishmania amazonensis wild type (La-WT) or arginase knocked out (La-arg−), using the untargeted Capillary Electrophoresis-Mass Spectrometry (CE-MS) approach to assess metabolomic profile. Macrophages showed specific changes in metabolite abundance upon Leishmania infection, as well as in the absence of parasite-arginase. The absence of L. amazonensis-arginase promoted the regulation of both host and parasite urea cycle, glycine and serine metabolism, ammonia recycling, metabolism of arginine, proline, aspartate, glutamate, spermidine, spermine, methylhistidine, and glutathione metabolism. The increased L-arginine, L-citrulline, L-glutamine, oxidized glutathione, S-adenosylmethionine, N-acetylspermidine, trypanothione disulfide, and trypanothione levels were observed in La-WT-infected C57BL/6-macrophage compared to uninfected. The absence of parasite arginase increased L-arginine, argininic acid, and citrulline levels and reduced ornithine, putrescine, S-adenosylmethionine, glutamic acid, proline, N-glutamyl-alanine, glutamyl-arginine, trypanothione disulfide, and trypanothione when compared to La-WT infected macrophage. Moreover, the absence of parasite arginase leads to an increase in NO production levels and a higher infectivity rate at 4 h of infection. The data presented here show a host-dependent regulation of metabolomic profiles of C57BL/6 macrophages compared to the previously observed BALB/c macrophages infected with L. amazonensis, an important fact due to the dual and contrasting macrophage phenotypes of those mice. In addition, the Leishmania-arginase showed interference with the urea cycle, glycine, and glutathione metabolism during host–pathogen interactions.

Cellular and immunological basis of the host-parasite relationship during infection withNeospora caninum

Parasitology ◽  
2006 ◽  
Vol 133 (3) ◽  
pp. 261-278 ◽  
Author(s):  
A. HEMPHILL ◽  
N. VONLAUFEN ◽  
A. NAGULESWARAN
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Neospora Caninum ◽  
Host Cells ◽  
Term Survival ◽  
Prevention Of Infection ◽  
Parasite Relationship ◽  
Potential Applications

Neospora caninumis an apicomplexan parasite that is closely related toToxoplasma gondii, the causative agent of toxoplasmosis in humans and domestic animals. However, in contrast toT. gondii, N. caninumrepresents a major cause of abortion in cattle, pointing towards distinct differences in the biology of these two species. There are 3 distinct key features that represent potential targets for prevention of infection or intervention against disease caused byN. caninum. Firstly, tachyzoites are capable of infecting a large variety of host cellsin vitroandin vivo. Secondly, the parasite exploits its ability to respond to alterations in living conditions by converting into another stage (tachyzoite-to-bradyzoite orvice versa). Thirdly, by analogy withT. gondii, this parasite has evolved mechanisms that modulate its host cells according to its own requirements, and these must, especially in the case of the bradyzoite stage, involve mechanisms that ensure long-term survival of not only the parasite but also of the host cell. In order to elucidate the molecular and cellular bases of these important features ofN. caninum, cell culture-based approaches and laboratory animal models are being exploited. In this review, we will summarize the current achievements related to host cell and parasite cell biology, and will discuss potential applications for prevention of infection and/or disease by reviewing corresponding work performed in murine laboratory infection models and in cattle.

scholarly journals Essential Role of Platelet-Activating Factor in Control of Leishmania (Leishmania)amazonensis Infection

2000 ◽  
Vol 68 (11) ◽  
pp. 6355-6361 ◽  
Author(s):  
Maria Valdrinez Campana Lonardoni ◽  
Momtchillo Russo ◽  
Sonia Jancar
Keyword(s):  
Lymph Nodes ◽  
Platelet Activating Factor ◽  
Parasite Load ◽  
Peritoneal Macrophages ◽  
Leishmania Infection ◽  
Prostaglandin E ◽  
No Production ◽  
Regional Lymph Nodes

ABSTRACT In the present study we investigated the role of platelet-activating factor (PAF) and prostaglandins in experimental Leishmania (Leishmania)amazonensis infection and the relationship between these mediators and nitric oxide (NO) production. Mouse peritoneal macrophages elicited with thioglicolate were infected with leishmania amastigotes, and the infection index determined 48 h later. The course of infection was monitored for 5 weeks in mice infected in the footpad with promastigotes by measuring the footpad swelling and parasite load in regional lymph nodes and spleen. The addition of PAF to C57BL/6 mouse macrophages significantly inhibited parasite growth and induced NO production. Treatment of macrophages with a selective PAF antagonist, WEB2086, increased the infection, indicating that endogenously produced PAF regulates macrophage ability to control leishmania infection. This effect of PAF was abolished by addition of the inhibitor of NO synthesis, L-NAME, to the cultures. The addition of prostaglandin E2 significantly increased the infection and NO production. Treatment with cyclo-oxygenase inhibitor, indomethacin, reduced the infection and PAF-induced release of NO. Thus, the increased NO production induced by PAF seems to be mediated by prostaglandins. The more-selective inhibitors of cyclo-oxygenase 2, nimesulide and NS-398, had no significant effect. Thus, antileishmanial activity correlates better with the presence of PAF or absence of prostaglandins than with NO production. In vivo treatment with PAF antagonists significantly increased leishmania lesions, as well as the parasite load, in regional lymph nodes and spleens. These findings indicate that PAF is essential for the control of leishmania infection.

scholarly journals Exploring Leishmania-Host Interaction with Reactome, a Database of Biological Pathways and Processes

2021 ◽  
Author(s):  
Julieth Irene Murillo Silva ◽  
Bijay Jassal ◽  
Maria Adelaida Gomez ◽  
Henning Hermjakob
Keyword(s):  
Clinical Manifestations ◽  
Host Cells ◽  
Leishmania Infection ◽  
Contextual Knowledge ◽  
Growth And Survival ◽  
Cell Recruitment ◽  
Host Interactions ◽  
Host Interaction ◽  
Wide Range ◽  
Infection Pathway

Leishmaniasis is a parasitic disease with a wide range of clinical manifestations. Multiple aspects of the Leishmania-host interaction, such as genetic factors and modulation of microbicidal functions in host cells, influence pathogenesis, disease severity and treatment outcome. How do scientists contend with this complexity? Here, we work towards representing detailed, contextual knowledge on Leishmania-host interactions in the Reactome pathway database to facilitate the extraction of novel mechanistic insights from existing datasets. The Reactome database uses a hierarchy of abstractions that allows for the incorporation of detailed contextual knowledge on biological processes matched to differentially expressed genes. It also includes tools for enhanced over-representation analysis that exploits this extra information. We conducted a systematic curation of published studies documenting different aspects of the Leishmania-host interaction. The 'Leishmania infection pathway' included four sub-pathways: phagocytosis, killing mechanisms, cell recruitment, and Leishmania parasite growth and survival. As proof-of-principle of the usefulness of the released pathway, we used it to analyze two previously released transcriptomic datasets of human and murine macrophages infected with Leishmania. Our results provide insights on the participation of ADORA2B signaling pathway in the modulation of IL10 and IL6 in infected macrophages. This work opens the way for other researchers to contribute to, and make use of, the Reactome database.

scholarly journals Nitrogen-Containing Metabolic Stressors Stimulate High-value Compounds Accumulation in Arthrospira platensis

2021 ◽  
Author(s):  
Farzaneh Fekrat ◽  
Maryam Shahbazi ◽  
Behnam Nami ◽  
Mohammad Amin Hejazi ◽  
Mohammad Reza Ghaffari
Keyword(s):  
Metabolic Networks ◽  
De Novo ◽  
Monosodium Glutamate ◽  
Arthrospira Platensis ◽  
Carotenoid Content ◽  
Acid Biosynthesis ◽  
De Novo Biosynthesis ◽  
Fatty Acid Accumulation ◽  
Acid Accumulation ◽  
Metabolite Abundance

Suitable conditions for high-value compounds hyperaccumulation are the most challenging approach in Arthrospira platensis. In the current study, the co-production of specialty pigments and high-value metabolites was investigated with a varying concentration of well-known and candidate metabolic stressors in Arthrospira platensis. Supplementing Arthrospira platensis with a minimum of 0.50% of Monosodium glutamate (MSG) and a maximum of 2% of aspartate (ASP) increased Phycocyanin productivity by 83.36 and 64.77 percent, respectively. However, a maximum of 1.50% of MSG and a minimum of 0.50% ASP increased carotenoid content by 188.80 and 68.97 percent, respectively. These observations, coupled with those showing supplemented ASP stimulate unsaturated fatty acid accumulation, possibly through enhanced de novo biosynthesis, and essential amino acid biosynthesis to a greater extent in Arthrospira platensis. A network correlation analysis also indicated the distinct metabolite abundance and the corresponding associated metabolic networks linked to pigment production in Arthrospira platensis.

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 Signal Regulatory Protein α Ligation Induces Macrophage Nitric Oxide Production through JAK/STAT- and Phosphatidylinositol 3-Kinase/Rac1/NAPDH Oxidase/H2O2-Dependent Pathways

2005 ◽  
Vol 25 (16) ◽  
pp. 7181-7192 ◽  
Author(s):  
Jacqueline Alblas ◽  
Henk Honing ◽  
Chantal Renardel de Lavalette ◽  
Marion H. Brown ◽  
Christine D. Dijkstra ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Regulatory Protein ◽  
Host Cells ◽  
No Production ◽  
Phosphatidylinositol 3 Kinase ◽  
Necrosis Factor Alpha ◽  
Cooperative Action ◽  
Factor Alpha ◽  
Oxide Synthase ◽  
Phosphatidylinositol 3

ABSTRACT Signal regulatory protein α (SIRPα) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2. In macrophages SIRPα can negatively regulate the phagocytosis of host cells and the production of tumor necrosis factor alpha. Here we provide evidence that SIRPα can also stimulate macrophage activities, in particular the production of nitric oxide (NO) and reactive oxygen species. Ligation of SIRPα by antibodies or soluble CD47 triggers inducible nitric oxide synthase expression and production of NO. This was not caused by blocking negative-regulatory SIRPα-CD47 interactions. SIRPα-induced NO production was prevented by inhibition of the tyrosine kinase JAK2. JAK2 was found to associate with SIRPα in macrophages, particularly after SIRPα ligation, and SIRPα stimulation resulted in JAK2 and STAT1 tyrosine phosphorylation. Furthermore, SIRPα-induced NO production required the generation of hydrogen peroxide (H2O2) by a NADPH oxidase (NOX) and the phosphatidylinositol 3-kinase (PI3-K)-dependent activation of Rac1, an intrinsic NOX component. Finally, SIRPα ligation promoted SHP-1 and SHP-2 recruitment, which was both JAK2 and PI3-K dependent. These findings demonstrate that SIRPα ligation induces macrophage NO production through the cooperative action of JAK/STAT and PI3-K/Rac1/NOX/H2O2 signaling pathways. Therefore, we propose that SIRPα is able to function as an activating receptor.

scholarly journals Nitric Oxide Production by the Human Intestinal Microbiota by Dissimilatory Nitrate Reduction to Ammonium

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Joan Vermeiren ◽  
Tom Van de Wiele ◽  
Willy Verstraete ◽  
Pascal Boeckx ◽  
Nico Boon
Keyword(s):  
Nitric Oxide ◽  
Nitrate Reduction ◽  
Fecal Microbiota ◽  
Host Cells ◽  
No Production ◽  
Gastrointestinal Microbiota ◽  
Dissimilatory Nitrate Reduction ◽  
Human Intestinal Microbiota ◽  
Gut Microorganisms

The free radical nitric oxide (NO) is an important signaling molecule in the gastrointestinal tract. Besides eukaryotic cells, gut microorganisms are also capable of producing NO. However, the exact mechanism of NO production by the gut microorganisms is unknown. Microbial NO production was examined under in vitro conditions simulating the gastrointestinal ecosystem using L-arginine or nitrate as substrates. L-arginine did not influence the microbial NO production. However, NO concentrations in the order of 90 ng NO-N per L feed medium were produced by the fecal microbiota from nitrate.N15tracer experiments showed that nitrate was mainly reduced to ammonium by the dissimilatory nitrate reduction to ammonium (DNRA) pathway. To our knowledge, this is the first study showing that gastrointestinal microbiota can generate substantial amounts of NO by DNRA and not by the generally accepted denitrification or L-arginine pathway. Further work is needed to elucidate the exact role between NO produced by the gastrointestinal microbiota and host cells.

scholarly journals Intracellular anti-leishmanial effect of Spergulin-A, a triterpenoid saponin of Glinus oppositifolius

2018 ◽  
Author(s):  
Saswati Banerjee ◽  
Niladri Mukherjee ◽  
Rahul L. Gajbhiye ◽  
Parasuraman Jaisankar ◽  
Sriparna Datta ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Leishmania Donovani ◽  
Host Cells ◽  
No Production ◽  
Triterpenoid Saponin ◽  
Immunostimulatory Activity ◽  
H Nmr ◽  
Intracellular Parasites ◽  
Tnf Α ◽  
Alternative Drugs

ABSTRACTMany of present chemotherapeutics are inadequate and also resistant against visceral leishmaniasis (VL) an immunosuppressive ailment caused by Leishmania donovani. Despite the interest in plant-based drug development, very few number of antileishmanial drugs from plant source is available. Glinus oppositifolius had been reported in favor of being immunomodulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. With this rationale, an n-BuOH fraction of the methanolic extract of the plant and obtained triterpenoid saponin Spergulin-A were evaluated against acellular and intracellular L. donovani. Immunostimulatory activity of them was confirmed by elevated TNF-α and extracellular NO production from treated MФs and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS, 13C, and 1H NMR. Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30μg/ml, the reduction was 92.6% after 72h. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. The results supported that G. oppositifolius and Spergulin-A can potentiate new lead molecules for the development of alternative drugs against VL.

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.

Interaction of Pneumocystis carinii with Host Lungs: an Ultrastructural Study

1980 ◽  
Vol 29 (2) ◽  
pp. 692-703 ◽  
Author(s):  
Kokichi Yoneda ◽  
Peter D. Walzer
Keyword(s):  
Pneumocystis Carinii ◽  
Host Cells ◽  
Type I ◽  
Tissue Fluid ◽  
Pulmonary Tissue ◽  
Corticosteroid Dose ◽  
Type Ii Pneumocytes ◽  
Parasite Relationship ◽  
Bleb Formation ◽  
Host Parasite

Pneumocystis carinii pneumonia was produced in rats by the administration of corticosteroids, low (8%) protein diet, and tetracycline in the drinking water. The rats were sacrificed at weekly intervals, and their lungs were examined by electron microscopy. For the first 6 weeks, few alterations were noted in host pulmonary tissue, except a close attachment of P. carinii trophozoites to the type I pneumocytes. At 7 to 8 weeks, when the infection reached the peak intensity on light microscopy, degenerative changes occurred in the type I pneumocyte, beginning with subepithelial bleb formation and followed by denudation of the basement membrane. This denuded surface appeared to be the site both of exudation of serum and tissue fluid into the alveolar space and of spread of P. carinii into the interstitium. There was hypertrophy of type II pneumocytes, which also occurred in uninfected control rats ingesting tetracyclines. With tapering of the corticosteroid dose, P. carinii was slowly cleared from the lungs, but latent infection persisted for at least 21 weeks. The host response to the corticosteroid dose tapering included increased prominence of alveolar macrophages and progressive interstitial lymphocytic infiltrate and fibrosis. Thus, P. carinii interacts with, and is associated with damage to, specific host cells. This interaction is important in the host-parasite relationship in this infection.

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