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Sex-specific modulation of the host transcriptome in the spleen of Schistosoma mansoni infected mice

ABSTRACT: Intestinal Schistosomiasis, caused by the helminth Schistosoma mansoni, results in fibroproliferative disease triggered by liver trapped parasite eggs. Characteristic of the infection is a chronic course of disease with progressive periportal fibrosis, spleno- and hepatomegaly, and portal hypertension. Despite significant progress in understanding the complex immunological processes involved in the host-pathogen relationship, there is currently no effective vaccine against the infection nor antifibrotic drugs, increasing the pressure to find new targets for schistosome drugs and vaccine candidates. We have recently reported that infection with male schistosomes can attenuate reinfections, while female schistosomes appear to weaken the host immune system. To decipher the underlying mechanisms of differential immunogenicity of female and male worms, we performed a comparative transcriptomic analysis of splenic tissue from unisexually and bisexually infected mice. We identified a total of 1293, 512 and 4062 genes, respectively, that were differentially expressed in the group of male-only (M), female-only (F) or bisexually (MF) infected mice compared to naive controls. Bisexual infection and infection with male worms showed the marked effects on host immune response, erythrocyte homeostasis, lipoprotein metabolism and cell cycle processes compared to the infection with female worms. Furthermore, we could show that both worm sexes trigger immune responses in an egg-independent manner, with a non-polarized Th1 and Th2 response, with female worms having a lower regulatory influence than males.

ORGANISM(S): Mus musculus

PROVIDER: GSE197804 | GEO | 2022/06/16

REPOSITORIES: GEO

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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:Schistosoma mansoni is one of the most common etiological agents responsible for the disease schistosomiasis. More than 200 million people suffer from this disease making it the most severe tropical disease after malaria in terms of morbidity. Praziquantel (PZQ) is the treatment of choice for schistosomiasis and has been used almost exclusively to treat the disease since the 1970s. However, while the drug is lethal for sexually mature schistosomes, it is ineffective against juveniles. Thus, while morbidity can be eased, a cure is difficult to achieve. As a result there is an urgent need to develop a new generation of anti-schistosomal drugs, a task that will be made easier by understanding the mechanism of action of PZQ. As yet, neither the molecule to which PZQ binds nor the means by which it kills mature schistosomes is known. The overarching aim of this study was to understand the molecular basis of PZQ sensitivity in S. mansoni. We believe that juvenile worms survive PZQ treatment in vivo due to the induction of, as yet, unidentified protective molecular pathways. To address this hypothesis juvenile and adult PR1 S. mansoni were treated in vitro with sub-lethal concentrations of PZQ. mRNA was extracted from replicate samples, cRNA prepagreen and labeled with cyanine dyes for analysis using a 44K S. mansoni microarray. The data was then analyzed using Genespring. Our findings suggest that a number of genes associated with drug transport, iron homeostasis and apoptosis are induced in juvenile but not adult schistosomes and that this allows the juvenile worms to protect themselves against the lethal effects of PZQ long enough for the drug to be metabolized by the human host. 42 days post exposure (DPE) male schistosomes were exposed to 0 and 1 µg/mL praziquantel (PZQ) for 1 or 20 h and 10 µg/mL PZQ for 1 h. 42 DPE female schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 20 h. 28 DPE mixed-sex schistosomes were exposed to 0, 1 and 10 µg/mL PZQ for 1 and 20 h. All experiments were performed in biological triplicates. The 0 µg/mL PZQ exposures were used as controls to the appropriate groups and a universal reference was used in all experiments that was comprised of RNA derived from 100 mixed sex, unexposed 42 DPE schistosomes spiked with 0.5 % (v/v) RNA isolated from 42 DPE mixed sex worms exposed to 10 µg/mL PZQ, 0.5 % (v/v) RNA isolated from 28 DPE worms exposed to 10 µg/mL PZQ and 0.5 % (v/v) RNA isolated from 28 DPE worms unexposed to PZQ. Transcriptional response to praziquantel exposure by time and concentration

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Sex-specific modulation of the host transcriptome in the spleen of Schistosoma mansoni infected mice

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