Evaluation of in vitro and in vivo immunostimulatory activities of poly (lactic-co-glycolic acid) nanoparticles loaded with soluble and autoclaved Leishmania infantum antigens: A novel vaccine candidate against visceral leishmaniasis

Primary and secondary unresponsiveness to meglumine has long been described in human visceral leishmaniasis. However, no studies have been performed to elucidate if these therapeutic failures were due to strain variability in meglumine sensitivity or were related to host factors. We have studied the in vitro sensitivity of 37 strains of Leishmania infantum isolated from 23 patients (11 human immunodeficiency virus-infected and 12 immunocompetent patients) with visceral leishmaniasis. Sensitivity tests were performed by infecting murine macrophages with Leishmania parasites and culturing them in medium containing different concentrations of meglumine. For each test we calculated a 50% effective dose (ED50) corresponding to the meglumine concentration at which 50% of the Leishmania parasites survived. In vitro results were strongly correlated to immediate clinical outcome. All strains requiring an ED50 of >70 microg/ml were related to therapeutic failures, whereas all strains requiring an ED50 of <40 microg/ml corresponded to an initial efficiency of meglumine. Among those patients who were initially improved, relapses occurred in all immunocompromised patients and in most immunocompetent patients who had a short duration of treatment (15 days). Finally, we found that in vitro sensitivity of strains decreased progressively in relapsing patients treated with meglumine. Consequently, the physician may be encouraged to alternate meglumine with other treatments such as amphotericin B or pentamidine, especially in the case of relapsing patients.

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Nanoliposomal Buparvaquone Immunomodulates Leishmania infantum-Infected Macrophages and Is Highly Effective in a Murine Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02297-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 12

Author(s):

Thais Alves da Costa-Silva ◽

Andrés Jimenez Galisteo ◽

José Angelo Lauletta Lindoso ◽

Leandro R. S. Barbosa ◽

Andre Gustavo Tempone

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Drug Repositioning ◽

Interleukin 10 ◽

Pcr Analysis ◽

Hydrodynamic Diameter ◽

Content Type ◽

Highly Effective

ABSTRACT Visceral leishmaniasis is a fatal parasitic neglected disease affecting 1.5 million people worldwide. Based on a drug repositioning approach, the aim of this work was to investigate the in vitro immunomodulatory potential of buparvaquone (BPQ) and to establish a safe regimen to evaluate the in vivo efficacy of BPQ entrapped by negatively charged nanoliposomes (BPQ-LP) in Leishmania infantum-infected hamsters. Small-angle X-ray scattering, dynamic light scattering, and the ζ-potential were applied in order to study the influence of BPQ on the liposome structure. Our data revealed that BPQ was located in the polar-apolar interface, snorkeling the polar region, and protected against aggregation inside the lipophilic region. The presence of BPQ also decreased the Z-average hydrodynamic diameter and increased the surface charge. Compared to intravenous and intramuscular administration, a subcutaneous route was a more effective route for BPQ-LP; at 0.4 mg/kg, BPQ-LP reduced infection in the spleen and liver by 98 and 96%, respectively. Treatment for 5 days resulted in limited efficacy, but 10 days of treatment resulted in an efficacy similar to that of a 15-day regimen. The nanoliposomal drug was highly effective, with a mean 50% effective dose of 0.25 mg/kg, reducing the parasite load in bone marrow by 80%, as detected using quantitative PCR analysis. In addition, flow cytometry studies showed that BPQ upregulated cytokines as tumor necrosis factor, monocyte chemoattractant protein 1, interleukin-10 (IL-10), and IL-6 in Leishmania-infected macrophages, eliminating the parasites via a nitric oxide-independent mechanism. This new formulation proved to be a safe and effective treatment for murine leishmaniasis that could be a useful candidate against visceral leishmaniasis.

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Ivermectin presents effective and selective antileishmanial activity in vitro and in vivo against Leishmania infantum and is therapeutic against visceral leishmaniasis

Experimental Parasitology ◽

10.1016/j.exppara.2020.108059 ◽

2021 ◽

Vol 221 ◽

pp. 108059

Author(s):

Thiago A.R. Reis ◽

João A. Oliveira-da-Silva ◽

Grasiele S.V. Tavares ◽

Débora V.C. Mendonça ◽

Camila S. Freitas ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Antileishmanial Activity

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Killed but Metabolically Active Leishmania infantum as a Novel Whole-Cell Vaccine for Visceral Leishmaniasis

Clinical and Vaccine Immunology ◽

10.1128/cvi.05660-11 ◽

2012 ◽

Vol 19 (4) ◽

pp. 490-498 ◽

Cited By ~ 22

Author(s):

Kevin W. Bruhn ◽

Ron Birnbaum ◽

Jacquelyn Haskell ◽

Veena Vanchinathan ◽

Stephanie Greger ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Parasitic Infection ◽

Cell Vaccine ◽

Vaccine Strategy ◽

Whole Cell ◽

Content Type ◽

Whole Cell Vaccine

ABSTRACTThere are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach usingLeishmania infantum chagasipromastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results inLeishmaniaorganisms termed killed but metabolically active (KBMA). In this report, we characterize thein vitrogrowth characteristics of both KBMAL. majorand KBMAL. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like liveL. infantum chagasi, KBMAL. infantum chagasiparasites were able to initially enter liver cellsin vivoafter intravenous infection. However, whereas liveL. infantum chagasiinfection leads to hepatosplenomegaly in mice after 6 months, KBMAL. infantum chagasiparasites were undetectable in the organs of mice at this time point.In vitro, KBMAL. infantum chagasiretained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMAL. infantum chagasicorrelated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either liveL. infantum chagasior KBMAL. infantum chagasidisplayed similar cytokine patternsin vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoanL. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens.

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Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis

Medical Microbiology and Immunology ◽

10.1007/s00430-021-00707-4 ◽

2021 ◽

Author(s):

Rafaella R. Costa ◽

João A. Oliveira-da-Silva ◽

Thiago A. R. Reis ◽

Grasiele S. V. Tavares ◽

Débora V. C. Mendonça ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Infantum ◽

Antileishmanial Activity

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Faculty Opinions recommendation of Luciferase-expressing Leishmania infantum allows the monitoring of amastigote population size, in vivo, ex vivo and in vitro.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.720295524.793509922 ◽

2015 ◽

Author(s):

Malcolm McConville

Keyword(s):

Population Size ◽

Leishmania Infantum ◽

Ex Vivo

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In vitro and in vivo inhibition of malaria parasite infection by monoclonal antibodies against Plasmodium falciparum circumsporozoite protein (CSP)

Scientific Reports ◽

10.1038/s41598-021-84622-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Merricka C. Livingstone ◽

Alexis A. Bitzer ◽

Alish Giri ◽

Kun Luo ◽

Rajeshwer S. Sankhala ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Monoclonal Antibodies ◽

Disease Burden ◽

Vaccine Candidate ◽

Specific Binding ◽

Circumsporozoite Protein ◽

Target Epitope ◽

Selection Of

AbstractPlasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA)n repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA)n epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA)n. In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.

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