Antileishmanial Effects of Synthetic Eh PIb Analogs Derived from the Entamoeba histolytica Lipopeptidephosphoglycan
| Autor: | Marie Groneberg, Joachim Clos, Julie Sellau, Siew Ling Choy, Stefan Hoenow, Nadine Kottmayr, Melina Mühlenpfordt, Hannelore Lotter, Helena Fehling, Frederic Ting, Chris Meier, Claudia Marggraff, Julia Eick, Dirk Landschulze, Sarah Corinna Lender, Eugenia Bifeld, Hannah Bernin |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
0303 health sciences biology Leishmaniasis medicine.disease biology.organism_classification Parasite load In vitro 03 medical and health sciences Entamoeba histolytica 0302 clinical medicine Infectious Diseases Immune system Cutaneous leishmaniasis In vivo medicine Pharmacology (medical) Leishmania major 030304 developmental biology 030215 immunology |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 64 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00161-20 |
| Popis: | With an estimated number of new cases annually of approximately 1.4 million, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks that urgently necessitate new drug development. A glycolipid molecule of the intestinal protozoan parasite Entamoeba histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of Entamoeba histolytica (EhPIb) subunit of the native compound and investigated their antileishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro In addition, topical application of the EhPIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in in vitro experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase-1 (Arg1) and interleukin 4 (IL-4), which are required by the parasites to circumvent their elimination by the immune response. The use of the host-targeting synthetic EhPIb compounds, either alone or in combination therapy with antiparasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease. |
| Databáze: | OpenAIRE |
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