Dataset Information

Comparative Metabonomic Investigations of Schistosoma japonicum From SCID Mice and BALB/c Mice: Clues to Developmental Abnormality of Schistosome in the Immunodeficient Host.

ABSTRACT: The growth and development of schistosome has been affected in the immunodeficient hosts. But it remains unresolved about the molecular mechanisms involved in the development and reproduction regulation of schistosomes. This study tested and compared the metabolic profiles of the male and female Schistosoma japonicum worms collected from SCID mice and BALB/c mice at 5 weeks post infection using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform, in which the worms from SCID mice were the investigated organisms and the worms from BALB/c mice were used as the controls. There were 1015 ion features in ESI+ mode and 342 ion features in ESI- mode were identified after filtration by false discovery rate. Distinct metabolic profiles were found to clearly differentiate both male and female worms in SCID mice from those in BALB/c mice using multivariate modeling methods including the Principal Component Analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA), and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). There were more differential metabolites in female worms than in male worms between SCID mice and BALB/c mice. And common and uniquely perturbed metabolites and pathways were identified among male and female worms from SCID mice when compared with BALB/c mice. The enriched metabolite sets of the differential metabolites in male worms between SCID mice and BALB/c mice included bile acid biosynthesis, taurine and hypotaurine metabolism, sphingolipid metabolism, retinol metabolism, purine metabolism, etc. And the enriched metabolite sets of differential metabolites in female worms included retinol metabolism, alpha linolenic acid and linoleic acid metabolism, purine metabolism, sphingolipid metabolism, glutamate metabolism, etc. Further detection and comparison in transcript abundance of genes of the perturbed retinol metabolism and its associated meiosis process in worms identified clues suggesting accumulated retinyl ester and perturbed meiotic process. These findings suggested an association between the schistosome with retarded growth and development in SCID mice and their perturbed metabolites and metabolic pathways, and provided a new insight into the growth and development regulation of S. japonicum worms from the metabolic level, which indicated great clues for discovery of drugs or vaccines against the parasites and disease with more researches.

SUBMITTER: Liu R

PROVIDER: S-EPMC6423161 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comparative Metabonomic Investigations of <i>Schistosoma japonicum</i> From SCID Mice and BALB/c Mice: Clues to Developmental Abnormality of Schistosome in the Immunodeficient Host.

Liu Rong R Cheng Wen-Jun WJ Tang Hong-Bin HB Zhong Qin-Ping QP Ming Zhen-Ping ZP Dong Hui-Fen HF

Frontiers in microbiology 20190312

The growth and development of schistosome has been affected in the immunodeficient hosts. But it remains unresolved about the molecular mechanisms involved in the development and reproduction regulation of schistosomes. This study tested and compared the metabolic profiles of the male and female <i>Schistosoma japonicum</i> worms collected from SCID mice and BALB/c mice at 5 weeks post infection using liquid chromatography tandem mass spectrometry (LC-MS/MS) platform, in which the worms from SCI ...[more]

PMID: 30915055

Similar Datasets

Project description:Schistosomiasis, caused by the parasitic flatworms called schistosomes, remains one of the most prevailing parasitic diseases in the world. The prodigious oviposition of female worms after maturity is the main driver of pathology due to infection, yet our understanding about the regulation of development and reproduction of schistosomes is limited. Here, we comparatively profiled the transcriptome of Schistosoma japonicum recovered from SCID and BALB/c mice, which were collected 35 days post-infection, when prominent morphological abnormalities could be observed in schistosomes from SCID mice, by performing RNA-seq analysis. Of the 11,183 identified genes, 62 differentially expressed genes (DEGs) with 39 upregulated and 23 downregulated messenger RNAs (mRNAs) were found in male worms from SCID mice (S_M) vs. male worms from BALB/c mice (B_M), and 240 DEGs with 152 upregulated and 88 downregulated mRNAs were found in female worms from SCID mice (S_F) vs. female worms from BALB/c mice (B_F). We also tested nine DEGs with a relatively higher expression abundance in the gonads of the worms (ovary, vitellaria, or testis), suggesting their potential biological significance in the development and reproduction of the parasites. Gene ontology (GO) enrichment analysis revealed that GO terms such as "microtubule-based process," "multicellular organismal development," and "Rho protein signal transduction" were significantly enriched in the DEGs in S_F vs. B_F, whereas GO terms such as "oxidation-reduction process," "response to stress," and "response to DNA damage stimulus" were significantly enriched in the DEGs in S_M vs. B_M. These results revealed that the differential expression of some important genes might contribute to the morphological abnormalities of worms in SCID mice. Furthermore, we selected one DEG, the mitochondrial prohibitin complex protein 1 (Phb1), to perform double-stranded RNA (dsRNA)-mediated RNA interference (RNAi) in vivo targeting the worms in BALB/c mice, and we found that it was essential for the growth and reproductive development of both male and female S. japonicum worms. Taken together, these results provided a wealth of information on the differential gene expression profiles of schistosomes from SCID mice when compared with those from BALB/c mice, which were potentially involved in regulating the growth and development of schistosomes. These findings contributed to an understanding of parasite biology and provided a rich resource for the exploitation of antischistosomal intervention targets.

Project description:Background: In immunodeficient mice, the growth and egg laying of schistosome were significantly retarded or inhibited, and their virulence on the host was also weakened. Some studies have suggested that host factors including endocrine and immune signals can modulate the parasite’s development and maturation. However, it is still not clear for the molecular mechanisms underlying the growth and maturation regulation of schistosome. Methodology/Principal results: We isolated the total RNAs of female and male schistosome from immunodeficient SCID mice and immunocompetent BALB/c mice (labeled as S_F, S_M, B_F and B_M) obtained at five weeks post infection with cercariae, and constructed cDNA libraries for RNA deep sequencing on an Illumina (Solexa) platform. In the results, the mRNAs were distinguished from long non-coding RNAs after blast to the reference Schistosoma japonicum genome, assemble and assessment of coding potential of the clean reads between S_F and B_F, and between S_M and B_M. The RNA-Seq yielded 90 to 142 million raw reads and 84 to 134 million clear reads per sample for the four schistosome samples. There are 56% to 65% of the clean reads mapped to the reference S. japonicum genome data. Given P-value <0.05, 298 differentially expressed genes (DEGs, mRNAs) for pairwise comparison of the above schistosome samples were identified. In detailed, 240 DEGs were identified in S_F vs B_F, of which 152 DEGs were up-regulated (147 DEGs were present in S_F worms but absent or undetected technically in B_F worms) and 88 were down-regulated (83 DEGs were present in B_F worms but absent or undetected technically in S_F worms). 62 DEGs were identified in S_M vs B_M, of which 39 were up-regulated (29 DEGs were present in S_M worms but absent or undetected technically in B_M worms) and 23 were down-regulated (22 DEGs were present in B_M worms but absent or undetected technically in S_M worms). Four differentially expressed mRNAs were shared among the two comparisons (present both in female and male worms), which were Sjp_0117620 (26S proteasome subunit P28-related), Sjp_0127870 (leucine zipper-EF-hand-containing transmembrane protein 1, mitochondrial precursor), Sjp_0130040 (putative dynein heavy chain) and Sjp_0094540 (hypothetical protein containing proteinase inhibitor I25, cystatin domain，SJCHGC07500 protein, partial). There were other 236 DEG specific in the comparison of S_F and B_F, and 58 DEG specific in the comparison of S_M and B_M. GO analysis was performed to summarize and explore the major GO categories of the DEGs which may be susceptible to host environments. The above DEGs of female comparison and male comparison were annotated with GO terms in three independent categories: biological processes (400 GO terms were hit for annotation of DEGs of female comparison and 287 GO terms were hit for annotation of DEGs of male comparison), molecular functions (231 GO terms were hit for annotation of DEGs of female comparison and 163 GO terms were hit for annotation of DEGs of male comparison), and cellular components (88 GO terms were hit for annotation of DEGs of female comparison and 75 GO terms were hit for annotation of DEGs of male comparison). The biological processes analysis revealed the predominant DEGs of female worms were involved in response to microtubule-based process, while predominant DEGs of male worms were involved in response to response to DNA damage stimulus, oxidation-reduction process and cellular response to stress. The molecular functions, some DEGs of female and male worms were annotated with calcium-dependent phospholipid binding activities in common. Notably, genes coding for microtubule associated complex, cytoskeletal part, cytoskeleton and microtubule cytoskeleton accounted for large portion of annotated DEGs of female worms in the cellular components analysis, while gene coding for nucleoplasmic THO complex of male worms were identified in the cellular components analysis. The KEGG pathway analysis showed many of the DEGs of female worms were involved in purine metabolism, RNA polymerase, fatty acid biosynthesis, fatty acid degradation and pyrimidine metabolism. Many of the DEGs of male worms were involved in oxidative phosphorylation, riboflavin metabolism and tyrosine metabolism. Conclusions/Significance: This study provides a comparative gene expression profiles of schistosomes derived from SCID mice and immunocompetent BALB/c mice. A number of genes potentially regulating the development of schistosomes were identified. These findings lay the foundation for schistosomiasis research in parasite-host interaction at the transcriptional level and provide a valuable resource for screening antischistosomal intervention targets or vaccine candidates.

Project description:BACKGROUND: More than 46 species of mammals can be naturally infected with Schistosoma japonicum in the mainland of China. Mice are permissive and may act as the definitive host of the life cycle. In contrast, rats are less susceptible to S. japonicum infection, and are considered to provide an unsuitable micro-environment for parasite growth and development. Since little is known of what effects this micro-environment has on the parasite itself, we have in the present study utilised a S. japonicum oligonucleotide microarray to compare the gene expression differences of 10-day-old schistosomula maintained in Wistar rats with those maintained in BALB/c mice. RESULTS: In total 3,468 schistosome genes were found to be differentially expressed, of which the majority (3,335) were down-regulated (? 2 fold) and 133 were up-regulated (? 2 fold) in schistosomula from Wistar rats compared with those from BALB/c mice. Gene ontology (GO) analysis revealed that of the differentially expressed genes with already established functions or close homology to well characterized genes in another organisms, many are related to important biological functions or molecular processes. Among the genes that were down-regulated in schistosomula from Wistar rats, some were associated with metabolism, signal transduction and development. Of these genes related to metabolic processes, areas including translation, protein and amino acid phosphorylation, proteolysis, oxidoreductase activities, catalytic activities and hydrolase activities, were represented. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of differential expressed genes indicated that of the 328 genes that had a specific KEGG pathway annotation, 324 were down-regulated and were mainly associated with metabolism, growth, redox pathway, oxidative phosphorylation, the cell cycle, ubiquitin-mediated proteolysis, protein export and the MAPK (mitogen-activated protein kinases) signaling pathway. CONCLUSIONS: This work presents the first large scale gene expression study identifying the differences between schistosomula maintained in mice and those maintained in rats, and specifically highlights differential expression that may impact on the survival and development of the parasite within the definitive host. The research presented here provides valuable information for the better understanding of schistosome development and host-parasite interactions.

Project description:Within the last decade there have been several severe combined immunodeficient (SCID) pig models discovered or genetically engineered. The animals have mutations in ARTEMIS, IL2RG, or RAG1/2 genes, or combinations thereof, providing SCID pigs with NK cells, but deficient in T and B cells, or deficient in NK, T, and B cells for research studies. Biocontainment facilities and positive pressure isolators are developed to limit pathogen exposure and prolong the life of SCID pigs. Raising SCID pigs in such facilities allows for completion of long-term studies such as xenotransplantation of human cells. Ectopically injected human cancer cell lines develop into tumors in SCID pigs, thus providing a human-sized in vivo model for evaluating imaging methods to improve cancer detection and therapeutic research and development. Immunocompromised pigs have the potential to be immunologically humanized by xenotransplantation with human hematopoietic stem cells, peripheral blood leukocytes, or fetal tissue. These cells can be introduced through various routes including injection into fetal liver or the intraperitoneal (IP) space, or into piglets by intravenous, IP, and intraosseous administration. The development and maintenance of transplanted human immune cells would be initially (at least) dependent on immune signaling from swine cells. Compared to mice, swine share higher homology in immune related genes with humans. We hypothesize that the SCID pig may be able to support improved engraftment and differentiation of a wide range of human immune cells as compared to equivalent mouse models. Humanization of SCID pigs would thus provide a valuable model system for researchers to study interactions between human tumor and human immune cells. Additionally, as the SCID pig model is further developed, it may be possible to develop patient-derived xenograft models for individualized therapy and drug testing. We thus theorize that the individualized therapeutic approach would be significantly improved with a humanized SCID pig due to similarities in size, metabolism, and physiology. In all, porcine SCID models have significant potential as an excellent preclinical animal model for therapeutic testing.

Project description:OBJECTIVE:Glucagon-like peptide-1 induces glucose-dependent insulin secretion and, in rodents, increases proliferation and survival of pancreatic beta cells. To investigate the effects on human beta cells, we used immunodeficient mice transplanted with human islets. The goal was to determine whether lixisenatide, a glucagon-like peptide-1 receptor agonist, improves human islet function and survival in vivo. METHODS:Five independent transplant studies were conducted with human islets from five individual donors. Diabetic human islet-engrafted immunodeficient mice were treated with lixisenatide (50, 150, and 500 µg/kg) or vehicle. Islet function was determined by blood glucose, plasma human insulin/C-peptide, and glucose tolerance tests. Grafts were analyzed for total beta- and alpha-cell number, percent proliferation, and levels of apoptosis. RESULTS:Diabetic mice transplanted with marginal human islet mass and treated with lixisenatide were restored to euglycemia more rapidly than vehicle-treated mice. Glucose tolerance tests, human plasma insulin, and glucose-stimulation indices of lixisenatide-treated mice were significantly improved compared to vehicle-treated mice. The percentages of proliferating or apoptotic beta cells at graft recovery were not different between lixisenatide-treated and vehicle-treated mice. Nevertheless, in one experiment we found a significant twofold to threefold increase in human beta-cell numbers in lixisenatide-treated compared to vehicle-treated mice. CONCLUSION:Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets. Because the proliferative capacity of human beta cells is limited, improved beta-cell survival coupled with enhanced beta-cell function following lixisenatide treatment may provide the greatest benefit for diabetic patients with reduced functional islet mass.

Dataset Information

Comparative Metabonomic Investigations of Schistosoma japonicum From SCID Mice and BALB/c Mice: Clues to Developmental Abnormality of Schistosome in the Immunodeficient Host.

Publications

Comparative Metabonomic Investigations of <i>Schistosoma japonicum</i> From SCID Mice and BALB/c Mice: Clues to Developmental Abnormality of Schistosome in the Immunodeficient Host.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets