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Visceral leishmaniasis (VL), caused by , is associated with parasite-induced immunological and physiological changes that ensure the survival of amastigotes within the host. Both the parasite and the host have nutritional requirements, and for auxotrophic , dependence on the host to supply specific growth requirements is essential. This highlights an intricate link between host immunity and metabolism during VL. This study explores the interplay between the host metabolome and immune responses pre- and post-infection and treatment, aiming to identify early metabolite markers of therapeutic success against . BALB/c mice infected with were divided into cured and non-cured groups based on treatment with a non-ionic surfactant vesicle formulation of sodium stibogluconate (300 mg Sb /kg, SSG-NIV) or PBS vehicle control. Specific immune responses were determined at day 21 and day 60 post-infection, and serum metabolite levels was measured using untargeted GC×GC-TOFMS metabolomics. Treatment effectively reduced parasite loads, triggering heightened CD4+ and CD8+ T-cell responses at day 21, with increased IFN-γ, IL-12, and IL-4, and decreased IL-10 and TGF-β. Pre-treatment metabolomics analysis identified changes in glycolysis, fatty acid and amino acid metabolism 1-week PI, suggesting an increased Warburg effect to supplement parasite survival and initiation of immune responses. Valine, lactic acid, and glycerol-1-oleate were identified as markers of early infection. Treatment with SSG-NIV altered metabolism of major macromolecules and the TCA cycle relative to non-cured groups. Additionally, glycine and ribitol show promise as immune correlates for antiparasitic therapies. These findings highlight the diagnostic and prognostic potential of serum-derived metabolites in monitoring host immune responses to VL and treatment.

Extracts from twelve samples of propolis collected from different regions of Libya were tested for their activity against Trypanosoma brucei, Leishmania donovani, Plasmodium falciparum, Crithidia fasciculata and Mycobacterium marinum and the cytotoxicity of the extracts was tested against mammalian cells. All the extracts were active to some degree against all of the protozoa and the mycobacterium, exhibiting a range of EC50 values between 1.65 and 53.6 μg/ml. The toxicity against mammalian cell lines was only moderate; the most active extract against the protozoan species, P2, displayed an IC50 value of 53.2 μg/ml. The extracts were profiled by using liquid chromatography coupled to high resolution mass spectrometry. The data sets were extracted using m/z Mine and the accurate masses of the features extracted were searched against the Dictionary of Natural Products (DNP). A principal component analysis (PCA) model was constructed which, in combination with hierarchical cluster analysis (HCA), divided the samples into five groups. The outlying groups had different sets of dominant compounds in the extracts, which could be characterised by their elemental composition. Orthogonal partial least squares (OPLS) analysis was used to link the activity of each extract against the different micro-organisms to particular components in the extracts.

Previous studies, using parenteral administration of antigen in lipid vesicles, have indicated a possible role for vesicle size in determining the Th1/Th2 bias of the resulting immune response. We have also demonstrated that the incorporation of bile salts into lipid vesicles (bilosomes) allows successful induction of mucosal and systemic immunity via the oral route. The following study was therefore carried out to determine whether size could also influence the Th1/Th2 bias in the immune response to bilosome entrapped influenza A antigen containing haemagglutinin administered by the oral route in the mouse and whether this could influence the disease process in the classical ferret model of disease. Consequently we produced two formulations of influenza A antigen entrapped in bilosomes: BV3 which contained a single population (range 10–100 nm, Z-average diameter 250 nm) and BV which had two populations (60–350 and 400–2500 nm, Z-average 980 nm). Following oral vaccination of BALB/c mice, BV was found to generate an immune response that had a significantly greater Th1 bias than BV3 as measured by serum IgG2a production and antigen-induced spleen cell IFN-γ production. In the traditional infection challenge model (ferrets) vaccination with BV (large) vesicles resulted in greater protection in terms of symptom-score and a higher responder number. However, both oral vaccine formulations were an improvement on intramuscular administration in terms of higher antibody production, lower temperatures, and reduced symptoms over time, post-infection. The results presented here demonstrate that oral vaccine formulations can be physically modified to manipulate resultant immune responses following vaccination and consequently can be designed to enhance the effectiveness of candidate vaccine antigens.

Previous studies infecting global IL-4Rα , IL-4 , and IL-13 mice on a BALB/c background with the visceralizing parasite have shown that the T helper 2 cytokines, IL-4, and IL-13, play influential but not completely overlapping roles in controlling primary infection. Subsequently, using macrophage/neutrophil-specific IL-4Rα deficient BALB/c mice, we demonstrated that macrophage/neutrophil unresponsiveness to IL-4 and IL-13 did not have a detrimental effect during infection. Here we expand on these findings and show that CD4 T cell-(Lck ), as well as pan T cell-(iLck ) specific IL-4Rα deficient mice, on a BALB/c background, unlike global IL-4Rα deficient mice, are also not adversely affected in terms of resistance to primary infection with . Our analysis suggested only a transient and tissue specific impact on disease course due to lack of IL-4Rα on T cells, limited to a reduced hepatic parasite burden at day 30 post-infection. Consequently, the protective role(s) demonstrated for IL-4 and IL-13 during infection are mediated by IL-4Rα-responsive cell(s) other than macrophages, neutrophils and T cells.

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world’s population is at risk of being infected with 0.7–1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950′s and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.

Despite advances in the treatment, the morbidity and mortality rate associated with invasive aspergillosis remains unacceptably high (70-90%) in immunocompromised patients. Amphotericin B (AMB), a polyene antibiotic with broad spectrum antifungal activity appears to be a choice of treatment but is available only as an intravenous formulation; development of an oral formulation would be beneficial as well as economical. Poly(lactide-co-glycolode) (PLGA) nanoparticles encapsulating AMB (AMB-NPs) were developed for oral administration. The AMB-NPs were 113 ± 20 nm in size with ~70% entrapment efficiency at 30% AMB w/w of polymer. The in vivo therapeutic efficacy of oral AMB-NPs was evaluated in neutropenic murine models of disseminated and invasive pulmonary aspergillosis. AMB-NPs exhibited comparable or superior efficacy to that of Ambisome® or Fungizone™ administered parenterally indicating potential of NPs as carrier for oral delivery. The present investigation describes an efficient way of producing AMB-NPs with higher AMB pay-load and entrapment efficiency employing DMSO as solvent and ethanol as non-solvent. The developed oral formulation was highly efficacious in murine models of disseminated aspergillosis as well as an invasive pulmonary aspergillosis, which is refractory to treatment with IP Fungizone™ and responds only modestly to AmBisome®.

Miltefosine (Milt) is the only oral treatment for visceral leishmaniasis (VL) but its use is associated with adverse effects, e.g., teratogenicity, vomiting, diarrhoea. Understanding how its chemical structure induces cytotoxicity, whilst not compromising its anti-parasitic efficacy, could identify more effective compounds. Therefore, we systemically modified the compound’s head, tail and linker tested the in vitro activity of three alkylphosphocholines (APC) series against Leishmania donovani strains with different sensitivities to antimony. The analogue, APC12, with an alkyl carbon chain of 12 atoms, was also tested for anti-leishmanial in vivo activity in a murine VL model. All APCs produced had anti-leishmanial activity in the micromolar range (IC50 and IC90, 0.46– > 82.21 µM and 4.14–739.89 µM; 0.01– > 8.02 µM and 0.09–72.18 µM, respectively, against promastigotes and intracellular amastigotes). The analogue, APC12 was the most active, was 4–10 fold more effective than the parent Milt molecule (APC16), irrespective of the strain’s sensitivity to antimony. Intravenous administration of 40 mg/kg APC12 to L. donovani infected BALB/c mice reduced liver and spleen parasite burdens by 60 ± 11% and 60 ± 19%, respectively, while oral administration reduced parasite load in the bone marrow by 54 ± 34%. These studies confirm that it is possible to alter the Milt structure and produce more active anti-leishmanial compounds.

Pharmacological probes are important tools for exploring disease biology and discovering new therapies. Often molecules of insufficient quality are used instead, leading to spurious and misleading results. The Boehringer Ingelheim open innovation portal opnMe.com addresses this deficiency by sharing extensively validated pharmacological probes with the scientific community.Pharmacological probes are important tools for exploring disease biology and discovering new therapies. Often molecules of insufficient quality are used instead, leading to spurious and misleading results. The Boehringer Ingelheim open innovation portal opnMe.com addresses this deficiency by sharing extensively validated pharmacological probes with the scientific community.

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.

Previous studies comparing interleukin 4 receptor α (IL-4Rα) -/- and interleukin 4 (IL-4) -/- BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13 -/- BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13 -/- mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L donovani-infected IL-13 -/- mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα -/- mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα -/- mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils.