Dataset Information

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites.

ABSTRACT: Triosephosphate isomerases (TPIs) from Taenia solium (TsTPI) and Schistosoma mansoni (SmTPI) are potential vaccine and drug targets against cysticercosis and schistosomiasis, respectively. This is due to the dependence of parasitic helminths on glycolysis and because those proteins elicit an immune response, presumably due to their surface localization. Here we report the crystal structures of TsTPI and SmTPI in complex with 2-phosphoglyceric acid (2-PGA). Both TPIs fold into a dimeric (?-?)8 barrel in which the dimer interface consists of ?-helices 2, 3, and 4, and swapping of loop 3. TPIs from parasitic helminths harbor a region of three amino acids knows as the SXD/E insert (S155 to E157 and S157 to D159 in TsTPI and SmTPI, respectively). This insert is located between ?5 and ?6 and is proposed to be the main TPI epitope. This region is part of a solvent-exposed 310-helix that folds into a hook-like structure. The crystal structures of TsTPI and SmTPI predicted conformational epitopes that could be used for vaccine design. Surprisingly, the epitopes corresponding to the SXD/E inserts are not the ones with the greatest immunological potential. SmTPI, but not TsTPI, habors a sole solvent exposed cysteine (SmTPI-S230) and alterations in this residue decrease catalysis. The latter suggests that thiol-conjugating agents could be used to target SmTPI. In sum, the crystal structures of SmTPI and TsTPI are a blueprint for targeted schistosomiasis and cysticercosis drug and vaccine development.

SUBMITTER: Jimenez-Sandoval P

PROVIDER: S-EPMC6980832 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites.

Jimenez-Sandoval Pedro P Castro-Torres Eduardo E González-González Rogelio R González-González Rogelio R Díaz-Quezada Corina C Gurrola Misraim M Camacho-Manriquez Laura D LD Leyva-Navarro Lucia L Brieba Luis G LG Brieba Luis G LG

PLoS neglected tropical diseases 20200110 1

Triosephosphate isomerases (TPIs) from Taenia solium (TsTPI) and Schistosoma mansoni (SmTPI) are potential vaccine and drug targets against cysticercosis and schistosomiasis, respectively. This is due to the dependence of parasitic helminths on glycolysis and because those proteins elicit an immune response, presumably due to their surface localization. Here we report the crystal structures of TsTPI and SmTPI in complex with 2-phosphoglyceric acid (2-PGA). Both TPIs fold into a dimeric (β-α)8 ba ...[more]

PMID: 31923219

Similar Datasets

Project description:Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

Project description:A study was carried out in Kamuli and Hoima districts in Eastern and Western regions of Uganda to determine the Taenia solium porcine cysticercosis (PCC) and gastrointestinal (GI) parasites co-infection status in pigs. One hundred sixty-one households were selected randomly and visited between November and December 2019. A household questionnaire was administered, and faecal and blood samples were collected from at least one pig older than 3 months per household. A blood sample was obtained from a jugular venipuncture, and a rectal faecal sample was obtained. Taenia spp. circulating antigen levels in the sample sera were tested using a commercial enzyme-linked immunosorbent assay kit, apDia™ cysticercosis Ag ELISA. The modified McMaster technique was used to identify and quantify the GI parasites. The apparent animal-level seroprevalence for PCC was 4.8% (95% CI 2.7-7.1) and differed across the two districts (p = 0.018). At the pig herd level, the prevalence was 9.7% (95% CI 5.5-14.4). The prevalence of the different nematode eggs and coccidian oocysts in the two districts was as follows: strongyles 79.0% (95% CI 74.3-83.6), coccidia 73.3% (95% CI 68.3-78.6), Trichuris spp. 7.4% (95% CI 4.9-10.6), Strongyloides ransomi 2.1 (95% CI 0.7-3.5) and Ascaris spp. 4.9 (95% CI 2.8-7.4). Overall, across the two districts, the arithmetic mean for the oocysts per gram (OPG) for coccidia was 2042.2 ± 5776.1, and eggs per gram (EPG) were the highest in strongyles 616.1 ± 991. Overall, 57.4% of the porcine cysticercosis seropositive pigs were also positive for at least one of the gastrointestinal helminths which included strongyles, Strongyloides ransomi, Trichuris spp. and Ascaris spp. The co-infection status of pigs with both PCC and GI parasites demonstrated by this study can provide an incentive for integrating the control and management of both parasites with oxfendazole. Further studies are required to understand the feasibility of using oxfendazole including cost-benefit analysis and the acceptability by local stakeholders for the control of T. solium cysticercosis and gastrointestinal parasites in pigs.

Dataset Information

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites.

Publications

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure