Virulence factors of Leishmania parasite: Their paramount importance in unraveling novel vaccine candidates and therapeutic targets

Kumari, Diksha; Mahajan, S.K.; Kour, Parampreet; Singh, Kuljit

doi:10.1016/j.lfs.2022.120829

Cited by 18 publications

(11 citation statements)

References 146 publications

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“…Among the proteins selected in our study was Serine/threonine kinase-like protein. Leishmania serine/threonine kinases, such as GSK-3, MAPKs and Aurora kinases, play an important role in the parasite’s survival and replication [ 97 ] and some of them have been proposed as potential vaccine candidates [ 98 ]. Finally, DNA-directed RNA polymerase-like protein has not yet been studied, to our knowledge, as a vaccine candidate or as part of chimeric vaccine candidates.…”

Section: Discussionmentioning

confidence: 99%

Immunoinformatics Approach to Design a Multi-Epitope Nanovaccine against Leishmania Parasite: Elicitation of Cellular Immune Responses

et al. 2023

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Leishmaniasis is a vector-borne disease caused by an intracellular parasite of the genus Leishmania with different clinical manifestations that affect millions of people worldwide, while the visceral form may be fatal if left untreated. Since the available chemotherapeutic agents are not satisfactory, vaccination emerges as the most promising strategy for confronting leishmaniasis. In the present study, a reverse vaccinology approach was adopted to design a pipeline starting from proteome analysis of three different Leishmania species and ending with the selection of a pool of MHCI- and MHCII-binding epitopes. Epitopes from five parasite proteins were retrieved and fused to construct a multi-epitope chimeric protein, named LeishChim. Immunoinformatics analyses indicated that LeishChim was a stable, non-allergenic and immunogenic protein that could bind strongly onto MHCI and MHCII molecules, suggesting it as a potentially safe and effective vaccine candidate. Preclinical evaluation validated the in silico prediction, since the LeishChim protein, encapsulated simultaneously with monophosphoryl lipid A (MPLA) into poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles, elicited specific cellular immune responses when administered to BALB/c mice. These were characterized by the development of memory CD4+ T cells, as well as IFNγ- and TNFα-producing CD4+ and CD8+ T cells, supporting the potential of LeishChim as a vaccine candidate.

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Section: Discussionmentioning

confidence: 99%

Immunoinformatics Approach to Design a Multi-Epitope Nanovaccine against Leishmania Parasite: Elicitation of Cellular Immune Responses

et al. 2023

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“…Promastigote molecules mediate the differentiation of infective forms in vectors and are vital to parasite survival during early infection phase, playing vital roles in their phagocytosis and recognition in dendrocytes, neutrophils, and macrophages and immune evasion as well as contributing to virulence of Leishmania spp. [36–38].…”

Section: Discussionmentioning

confidence: 99%

Leishmaniinae: evolutionary inferences based on protein expression profiles (PhyloQuant) congruent with phylogenetic relationships amongLeishmania, Endotrypanum, Porcisia, Zelonia, Crithidia,andLeptomonas

Mule,

Alemán,

Fernandes

et al. 2023

Preprint

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Evolutionary relationships among parasites of the subfamily Leishmaniinae, which comprises pathogen agents of leishmaniasis, were inferred based on differential protein expression profiles from mass spectrometry-based quantitative data using the PhyloQuant method. Evolutionary distances following identification and quantification of protein and peptide abundances using Proteome Discoverer (PD) and MaxQuant (MQ) softwares were estimated for 11 species from 6 Leishmaniinae genera. Results clustered all dixenous species of the genus Leishmania, subgenera L. (Leishmania), L. (Viannia) and L. (Mundinia), sister to the dixenous species of genera Endotrypanum and Porcisia. Positioned basal to the assemblage formed by all these parasites were the species of genera Zelonia, Crithidia and Leptomonas, so far described as monoxenous of insects although eventually reported from humans. Inferences based on protein expression profiles were congruent with currently established phylogeny using DNA sequences. Our results reinforce PhyloQuant as a valuable approach to infer evolutionary relationships consistent with genera, subgenera, and species-specific biological characteristics, able to resolve within Leishmaniinae, which is comprised of very tightly related trypanosomatids that are just beginning to be phylogenetically unravelled. In additional to evolutionary history, mapping of species-specific protein expression is paramount to understand differences in infection processes, disease presentations, tissue tropisms, potential to jump from insects to vertebrates including humans, and potential targets for species-specific diagnostic and drug development. Keywords: Evolution, Leishmaniasis, Leishmaniinae, PhyloQuant, proteome, taxonomy, tropical diseases, Trypanosomatidae

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“…For several other protozoa-associated diseases, in particular those classified as neglected tropical diseases (NTDs) [ 3 ], there are fewer therapeutic options. Examples are African sleeping sickness, Chagas disease, and visceral leishmaniasis, which result from infections with trypanosomatids, namely Trypanosoma brucei , T. cruzi and Leishmania donovani [ 4 , 5 , 6 ]. The currently approved trypanocidal drugs exhibit severe side effects, which limit their use [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Generation of Aurachin Derivatives by Whole-Cell Biotransformation and Evaluation of Their Antiprotozoal Properties

et al. 2023

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The natural product aurachin D is a farnesylated quinolone alkaloid, which is known to possess activity against the causative agent of malaria, Plasmodium spp. In this study, we show that aurachin D inhibits other parasitic protozoa as well. While aurachin D had only a modest effect on Trypanosoma brucei rhodesiense, two other trypanosomatids, T. cruzi and Leishmania donovani, were killed at low micromolar and nanomolar concentrations, respectively, in an in vitro assay. The determined IC50 values of aurachin D were even lower than those of the reference drugs benznidazole and miltefosine. Due to these promising results, we set out to explore the impact of structural modifications on the bioactivity of this natural product. In order to generate aurachin D derivatives with varying substituents at the C-2, C-6 and C-7 position of the quinolone ring system, we resorted to whole-cell biotransformation using a recombinant Escherichia coli strain capable of aurachin-type prenylations. Quinolone precursor molecules featuring methyl, methoxy and halogen groups were fed to this E. coli strain, which converted the substrates into the desired analogs. None of the generated derivatives exhibited improved antiprotozoal properties in comparison to aurachin D. Obviously, the naturally occurring aurachin D features already a privileged structure, especially for the inhibition of the causative agent of visceral leishmaniasis.

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Virulence factors of Leishmania parasite: Their paramount importance in unraveling novel vaccine candidates and therapeutic targets

Cited by 18 publications

References 146 publications

Immunoinformatics Approach to Design a Multi-Epitope Nanovaccine against Leishmania Parasite: Elicitation of Cellular Immune Responses

Immunoinformatics Approach to Design a Multi-Epitope Nanovaccine against Leishmania Parasite: Elicitation of Cellular Immune Responses

Leishmaniinae: evolutionary inferences based on protein expression profiles (PhyloQuant) congruent with phylogenetic relationships amongLeishmania, Endotrypanum, Porcisia, Zelonia, Crithidia,andLeptomonas

Generation of Aurachin Derivatives by Whole-Cell Biotransformation and Evaluation of Their Antiprotozoal Properties

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