Vaccination with Recombinant Leishmania donovani Gamma-Glutamylcysteine Synthetase Fusion Protein Protects Against L. donovani Infection

Henriquez, Fiona L.; Campbell, Samantha A; Roberts, Craig W.; Mullen, Alexander B.; Burchmore, Richard; Carter, K C

doi:10.1645/ge-2360.1

Cited by 12 publications

(5 citation statements)

References 17 publications

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“…This factor may be multiplied by protein/peptide abundance to derive an “effective concentration” of a particular peptide. A high effective concentration may be the reason underlying the efficacy of leishmanial γ-glutamylcysteine synthetase as an effective vaccine in animal models of Leishmania donovani infection (77, 78). Alternatively, this antigen may be more abundantly expressed in L. donovani than suggested by the data derived from L. mexicana that were used here for illustration.…”

Section: Reflections On Improving Reverse Vaccinology Approaches For mentioning

confidence: 99%

Leishmania spp. Proteome Data Sets: A Comprehensive Resource for Vaccine Development to Target Visceral Leishmaniasis

Aebischer

2014

Front. Immunol.

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Visceral leishmaniasis is a neglected infectious disease caused primarily by Leishmania donovani and Leishmania infantum protozoan parasites. A significant number of infections take a fatal course. Drug therapy is available but still costly and parasites resistant to first line drugs are observed. Despite many years of trial no commercial vaccine is available to date. However, development of a cost effective, needle-independent vaccine remains a high priority. Reverse vaccinology has attracted much attention since the term has been coined and the approach tested by Rappuoli and colleagues. This in silico selection of antigens from genomic and proteomic data sets was also adapted to aim at developing an anti-Leishmania vaccine. Here, an analysis of the efforts is attempted and the challenges to be overcome by these endeavors are discussed. Strategies that led to successful identification of antigens will be illustrated. Furthermore, these efforts are viewed in the context of anticipated modes of action of effective anti-Leishmania immune responses to highlight possible advantages and shortcomings.

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Section: Reflections On Improving Reverse Vaccinology Approaches For mentioning

confidence: 99%

Leishmania spp. Proteome Data Sets: A Comprehensive Resource for Vaccine Development to Target Visceral Leishmaniasis

Aebischer

2014

Front. Immunol.

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“…L -buthionine- S , R -sulfoximine (BSO), a specific inhibitor of Gcs cures and prolongs survival of mice infected with T. brucei implicating Gcs as a potential drug target [24] . It was also observed that vaccination with L. donovani Gcs (LdGcs) fusion protein or DNA based vaccine provided protection against L. donovani infection in BALB/c mouse model which further validates the pharmaceutical importance of Gcs [25] , [26] .…”

Section: Introductionmentioning

confidence: 74%

Biochemical and biophysical characterization of Leishmania donovani gamma-glutamylcysteine synthetase

Agnihotri

Singh

Shakya

et al. 2016

Biochemistry and Biophysics Reports

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γ-glutamylcysteine synthetase (Gcs) is a vital enzyme catalyzing the first and rate limiting step in the trypanothione biosynthesis pathway, the ATP-dependent ligation of L-Glutamate and L-Cysteine to form gamma-glutamylcysteine. The Trypanothione biosynthesis pathway is unique metabolic pathway essential for trypanosomatid survival rendering Gcs as a potential drug target. Here we report the cloning, expression, purification and characterization of L. donovani Gcs. Three other constructs of Gcs (GcsN, GcsC and GcsT) were designed on the basis of S. cerevisiae and E. coli Gcs crystal structures. The study shows Gcs possesses ATPase activity even in the absence of substrates L-glutamate and L-Cysteine. Divalent ions however plays an indispensable role in LdGcs ATPase activity. Isothermal titration calorimetry and fluorescence studies illustrates that L. donovani Gcs binds substrate in order ATP >L-glutamate>L-cysteine with Glu 92 and Arg 498 involved in ATP hydrolysis and Glu 92, Glu 55 and Arg 498 involved in glutamate binding. Homology modeling and molecular dynamic simulation studies provided the structural rationale of LdGcs catalytic activity and emphasized on the possibility of involvement of three Mg2+ ions along with Glutamates 52, 55, 92, 99, Met 322, Gln 328, Tyr 397, Lys 483, Arg 494 and Arg 498 in the catalytic function of L. donovani Gcs.

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“…Vesicle delivery systems are also being considered for VL vaccines and have been shown to adjuvant protein antigens and induce sustained Th1 immune responses [103]. These delivery systems have shown some protection against L. donovani infection in experimental mouse models [104] and provide a new approach to the development of VL vaccines. …”

Section: Second-generation Vaccinesmentioning

confidence: 99%

Development of Vaccines against Visceral Leishmaniasis

Evans

Kędzierski

2012

Journal of Tropical Medicine

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Leishmaniasis is a neglected disease resulting in a global morbidity of 2,090 thousand Disability-Adjusted Life Years and a mortality rate of approximately 60,000 per year. Among the three clinical forms of leishmaniasis (cutaneous, mucosal, and visceral), visceral leishmaniasis (VL) accounts for the majority of mortality, as if left untreated VL is almost always fatal. Caused by infection with Leishmania donovani or L. infantum, VL represents a serious public health problem in endemic regions and is rapidly emerging as an opportunistic infection in HIV patients. To date, no vaccine exists for VL or any other form of leishmaniasis. In endemic areas, the majority of those infected do not develop clinical symptoms and past infection leads to robust immunity against reinfection. Thus the development of vaccine for Leishmania is a realistic public health goal, and this paper summarizes advances in vaccination strategies against VL.

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Vaccination with Recombinant Leishmania donovani Gamma-Glutamylcysteine Synthetase Fusion Protein Protects Against L. donovani Infection

Cited by 12 publications

References 17 publications

Leishmania spp. Proteome Data Sets: A Comprehensive Resource for Vaccine Development to Target Visceral Leishmaniasis

Leishmania spp. Proteome Data Sets: A Comprehensive Resource for Vaccine Development to Target Visceral Leishmaniasis

Biochemical and biophysical characterization of Leishmania donovani gamma-glutamylcysteine synthetase

Development of Vaccines against Visceral Leishmaniasis

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