Search results for "LEISHMANIASIS"

Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

2018

Abstract: Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2‐substituted‐1H‐benzo[d]imidazole derivatives (9ad) showing affinity in the submicromolar range (Ki = 0.150.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intrace…

Screening sierologico per Leishmania infantum su donatori di sangue e HIV+ asintomatici residenti in area endemica [Serological screening for Leishma…

2008

Visceral leishmaniasis (VL) is endemic in Sicily (48 new cases in 2004, of which nine were in Agrigento). In southern Europe between 25-70 per cent of adult VL cases are related to HIV infection. The HIV cases have a high risk (1.5-9%) of developing VL either as a new infection or as the revival of a latent infection. We therefore carried out serologic screening to detect antibodies against L. infantum by IFAT in 1449 blood donors in Agrigento and the surrounding area (May-December 2005) and in 120 HIV+ in western Sicily, all of whom were asymptomatic and had no history of VL. L. DNA was assessed by nested PCR in blood samples of some seropositive donors. Of the 1449 blood donors, 11 (0.75%…

Serological screening for Leishmania infantum in asymptomatic blood donors living in an endemic area (Sicily, Italy)

2005

The purpose of our study was to assess whether Leishmania infantum parasitemia occurs in asymptomatic Leishmania-seropositive subjects. Samples from 500 blood donors were tested using an enzyme-linked immunosorbent assay (ELISA). Anti-Leishmania antibodies were not found in any sample. Our findings suggest that the risk of L. infantum transmission by blood transfusion in Sicily is very low.

Topical treatment with a two-component gel releasing nitric oxide cures C57BL/6 mice from cutaneous leishmaniasis caused by Leishmania major.

2016

Cutaneous leishmaniasis: Distinct functions of dendritic cells and macrophages in the interaction of the host immune system with Leishmania major

2017

Leishmaniasis is transmitted by sand flies leading to parasite inoculation into skin. In the mammalian host, the parasite primarily resides in skin macrophages (MΦ) and dendritic cells (DC). MΦ are silently invaded by the parasite eliciting a stress response, whereas DC become activated, release IL-12, and prime antigen-specific T cells. Here we review the basics of the immune response against this human pathogen and elucidate the role and function DC and MΦ for establishment of protective immunity against leishmaniasis. We focus on cell type-specific differences in parasite uptake, phagocyte activation and processing of parasite antigens to facilitate an understanding how their respective …

Interleukin 1α Promotes Th1 Differentiation and Inhibits Disease Progression in Leishmania major–susceptible BALB/c Mice

2003

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in l…

Deficiency in the Transcription Factor Interferon Regulatory Factor (Irf)-2 Leads to Severely Compromised Development of Natural Killer and T Helper …

2000

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for…

Miltefosine Efficiently Eliminates Leishmania major Amastigotes from Infected Murine Dendritic Cells without Altering Their Immune Functions▿

2009

ABSTRACT As a treatment for leishmaniasis, miltefosine exerts direct toxic effects on the parasites. Miltefosine also modulates immune cells such as macrophages, leading to parasite elimination via oxidative radicals. Dendritic cells (DC) are critical for initiation of protective immunity against Leishmania through induction of Th1 immunity via interleukin 12 (IL-12). Here, we investigated the effects of miltefosine on DC in Leishmania major infections. When cocultured with miltefosine for 4 days, the majority of in vitro -infected DC were free of parasites. Miltefosine treatment did not influence DC maturation (upregulation of major histocompatibility complex II [MHC II] or costimulatory m…

Cathepsin B in Antigen-Presenting Cells Controls Mediators of the Th1 Immune Response during Leishmania major Infection

2014

Resistance and susceptibility to Leishmania major infection in the murine model is determined by the capacity of the host to mount either a protective Th1 response or a Th2 response associated with disease progression. Previous reports involving the use of cysteine cathepsin inhibitors indicated that cathepsins B (Ctsb) and L (Ctsl) play important roles in Th1/Th2 polarization during L. major infection in both susceptible and resistant mouse strains. Although it was hypothesized that these effects are a consequence of differential patterns of antigen processing, the mechanisms underlying these differences were not further investigated. Given the pivotal roles that dendritic cells and macrop…

Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

2018

Abstract: In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8CTE, fused benzo[b]thiophenes and ,'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%-90% inhibition of the target enzyme at 20m). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-to…