Development of Vaccines against Visceral Leishmaniasis

Evans, Krystal J.; Kędzierski, Łukasz

doi:10.1155/2012/892817

Cited by 66 publications

(56 citation statements)

References 143 publications

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“…L. donovani and L. infantum coinfection with HIV has now been recognised as a significant clinical problem [166]. Compared to other coinfections, a higher mortality rate has been reported in AIDS patients coinfected with L. donovani or L. infantum [167].…”

Section: Methodsmentioning

confidence: 99%

Immune Regulation during Chronic Visceral Leishmaniasis

et al. 2014

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Visceral leishmaniasis is a chronic parasitic disease associated with severe immune dysfunction. Treatment options are limited to relatively toxic drugs, and there is no vaccine for humans available. Hence, there is an urgent need to better understand immune responses following infection with Leishmania species by studying animal models of disease and clinical samples from patients. Here, we review recent discoveries in these areas and highlight shortcomings in our knowledge that need to be addressed if better treatment options are to be developed and effective vaccines designed.

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Section: Methodsmentioning

confidence: 99%

Immune Regulation during Chronic Visceral Leishmaniasis

et al. 2014

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“…Drugs used for chemotherapy of leishmaniasis are toxic, and no licensed vaccine is available (18,19). Incidentally, Leishmania lacks a complete heme biosynthetic pathway (20); therefore, a heme acquisition process from extracellular milieu is essential for the parasites (21).…”

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confidence: 99%

Functional Characterization of Monomeric GTPase Rab1 in the Secretory Pathway of Leishmania

Bahl

Parashar

Malhotra

et al. 2015

Journal of Biological Chemistry

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Leishmania secretes a large number of its effectors to the extracellular milieu. However, regulation of the secretory pathway in Leishmania is not well characterized. Here, we report the cloning, expression, and characterization of the Rab1 homologue from Leishmania. We have found that LdRab1 localizes in Golgi in Leishmania. To understand the role of LdRab1 in the secretory pathway of Leishmania, we have generated transgenic parasites overexpressing GFP-LdRab1:WT, GFP-LdRab1:Q67L (a GTPase-deficient dominant positive mutant of Rab1), and GFP-LdRab1:S22N (a GDP-locked dominant negative mutant of Rab1). Surprisingly, our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N does not disrupt the trafficking and localization of hemoglobin receptor in Leishmania. To determine whether the Rab1-dependent secretory pathway is conserved in parasites, we have analyzed the role of LdRab1 in the secretion of secretory acid phosphatase and Ldgp63 in Leishmania. Our results have shown that overexpression of GFP-LdRab1:Q67L or GFP-LdRab1:S22N significantly inhibits the secretion of secretory acid phosphatase by Leishmania. We have also found that overexpression of GFP-LdRab1: Q67L or GFP-LdRab1:S22N retains RFP-Ldgp63 in Golgi and blocks the secretion of Ldgp63, whereas the trafficking of RFPLdgp63 in GFP-LdRab1:WT-expressing cells is unaltered in comparison with control cells. Taken together, our results have shown that the Rab1-regulated secretory pathway is well conserved, and hemoglobin receptor trafficking follows an Rab1-independent secretory pathway in Leishmania.Small GTPases of the Rab family are master regulators of intracellular trafficking (1). These proteins are localized on specific compartments and regulate the transport through fusion between two compartments in a nucleotide-dependent process (2, 3). About 70 Rab proteins are identified in mammalian cells. In the endocytic pathway, Rab5 is present in the sorting endosome, whereas Rab4 and Rab11 are localized in recycling endosomes (4, 5). Rab7, Rab9, and Rab24 are associated with the late endosomal compartment. Rab7 mediates transport from the late endosomes to lysosomes, whereas Rab9 regulates the trafficking of lysosomal enzymes from the trans-Golgi network to lysosomes (6 -9). In the secretory pathway, Rab1 regulates the anterograde transport from the endoplasmic reticulum (ER) 3 to the Golgi (10), whereas retrograde transport from Golgi to ER is mediated by Rab2 (11). Rab6 localizes in the Golgi and is involved in intra-Golgi trafficking (12). Moreover, Rab18, Rab30, and Rab43 are found to be important for maintaining Golgi structure (13,14). In addition, transport of cargo from the Golgi to the cell surface is regulated by different Rabs. For example, Rab3 plays a role in release of neurotransmitter, Rab27 regulates the trafficking of lytic granules and melanosomes toward the plasma membrane, and Rab8 is involved in regulating the traffic from the trans-Golgi network to the plasma membrane (15). However, the secretory pathway is n...

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“…In addition, there is evidence of increasing problems with resistance in pathogens against a broad range of chemotherapeutic agents, compromising the treatment of infectious diseases. [3] Moreover, in spite of major efforts, there are very few examples of success in developing new drugs and vaccines against eukaryotic pathogens, [4,5] indicating that alternative methods are needed at a time of major advances in molecular and computer technologies. In our opinion, the development of new treatments requires a detailed understanding of pathogens, host interactions and the molecular processes of disease.…”

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confidence: 99%

The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

et al. 2014

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1Mason et al. Structures of parasite proteinsNew interventions against infectious diseases require a detailed knowledge and understanding of pathogen-host interactions and pathogeneses at the molecular level. The combination of the considerable advances in systems biology research with methods to explore the structural biology of molecules is poised to provide new insights into these areas. Importantly, exploring threedimensional structures of proteins is central to understanding disease processes, and establishing structure-function relationships assists in identification and assessment of new drug and vaccine targets. Frequently, the molecular arsenal deployed by invading pathogens, and in particular parasites, reveals a common theme whereby families of proteins with conserved three-dimensional folds play crucial roles in infectious processes, but individual members of such families show high levels of specialisation which is often achieved through grafting particular structural features onto the shared overall fold. Accordingly, the applicability of predictive methodologies based on the primary structure of proteins or genome annotations is limited, particularly when thorough knowledge of molecular level mechanisms is required. Such instances exemplify the need for experimental threedimensional structures provided by protein crystallography, which remain an essential component of this area of research. In the present article, we review two examples of key protein families recently investigated in our laboratories, which could represent intervention targets in the metabolome or secretome of parasites. IntroductionInfectious diseases caused by eukaryotic pathogens represent a major disease burden to humans world-wide. In the absence of effective preventative approaches and new intervention strategies, this burden is likely to increase further, [1,2] compounded by food and water shortages, economic crises, wars and climate change, particularly in disadvantaged countries. In addition, there is evidence of increasing problems with resistance in pathogens against a broad range of chemotherapeutic agents, compromising the treatment of infectious diseases. [3] Moreover, in spite of major efforts, there are very few examples of success in developing new drugs and vaccines against eukaryotic pathogens, [4,5] indicating that alternative methods are needed at a time of major advances in molecular and computer technologies. In our opinion, the development of new treatments requires a detailed understanding of pathogens, host interactions and the molecular processes of disease. For instance, knowledge of the three-dimensional structures of proteins with pivotal roles in disease, and the probing of their underlying biology are crucial for understanding the pathogenesis. Through establishing the relevant structure-function relationships, one can elucidate how individual proteins function, so that new ways of disrupting relevant pathways can be found, in order to facilitate the identification of new drug and vaccine targets. ...

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Development of Vaccines against Visceral Leishmaniasis

Cited by 66 publications

References 143 publications

Immune Regulation during Chronic Visceral Leishmaniasis

Immune Regulation during Chronic Visceral Leishmaniasis

Functional Characterization of Monomeric GTPase Rab1 in the Secretory Pathway of Leishmania

The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

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