Schistosomiasis is one of the most prevalent parasitic diseases worldwide and is a public health problem. Schistosoma mansoni is the most widespread species responsible for schistosomiasis in the Americas, Middle East and Africa. Adult female worms (mated to males) release eggs in the hepatic portal vasculature and are the principal cause of morbidity. Comparative separate transcriptomes of female and male adult worms were previously assessed with using microarrays and Serial Analysis of Gene Expression (SAGE), thus limiting the possibility of finding novel genes. Moreover, the egg transcriptome was analyzed only once with limited bacterially cloned cDNA libraries. To compare the gene expression of S. mansoni eggs, females, and males, we performed RNA-Seq on these three parasite forms using 454/Roche technology and reconstructed the transcriptome using Trinity de novo assembly. The resulting contigs were mapped to the genome and were cross-referenced with predicted Smp genes and H3K4me3 ChIP-Seq public data. For the first time, we obtained separate, unbiased gene expression profiles for S. mansoni eggs and female and male adult worms, identifying enriched biological processes and specific enriched functions for each of the three parasite forms. Transcripts with no match to predicted genes were analyzed for their protein-coding potential and the presence of an encoded conserved protein domain. A set of 232 novel protein-coding genes with putative functions related to reproduction, metabolism, and cell biogenesis was detected, which contributes to the understanding of parasite biology. Large-scale RNA-Seq analysis using de novo assembly associated with genome-wide information for histone marks in the vicinity of gene models constitutes a new approach to transcriptome analysis that has not yet been explored in schistosomes. Importantly, all data have been consolidated into a UCSC Genome Browser search- and download-tool (http://schistosoma.usp.br/). This database provides new ways to explore the schistosome genome and transcriptome and will facilitate molecular research on this important parasite. Schistosomiasis is a public health problem caused by parasites of the genus Schistosoma, of which S. mansoni is the primary causative agent. The parasite has a complex life cycle; their sexual reproductive stage is dependent on female and male adult worms mating inside the mesenteric circulation of the human host, with the female releasing hundreds of eggs daily. This phase of the life cycle is responsible for the development of pathology, which is proportional to the number of eggs accumulating in the liver and intestine of the human host. Genome and transcriptome sequencing of this parasite represent important advances in schistosome research, but there is still a need for integrated analyses to better understand the biology of this parasite. In this study, we describe the first large-scale transcriptomes of eggs, and female and male adult worms, the parasite forms that are mainly responsible for the pathology of schistosomiasis. We were able to cross-reference the gene transcription regions with promoter regions, thus improving the gene annotations. Moreover, we identified the expression of novel protein-coding genes not yet described in the current genome annotation, advancing the biological knowledge regarding this parasite.

Chikungunya virus (CHIKV) is a re-emergent arthropod-borne virus (arbovirus) that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia. In the last decade, CHIKV has become a serious public health problem causing several outbreaks around the world. Despite the fact that CHIKV has been around since 1952, our knowledge about immunopathology, innate and adaptive immune response involved in this infectious disease is incomplete. In this review, we provide an updated summary of the current knowledge about immune response to CHIKV and about soluble immunological markers associated with the morbidity, prognosis and chronicity of this arbovirus disease. In addition, we discuss the progress in the research of new vaccines for preventing CHIKV infection and the use of monoclonal antibodies as a promising therapeutic strategy.

Eukaryotic genomes are transcribed into numerous regulatory long non-coding RNAs (lncRNAs). Compared to mRNAs, lncRNAs display higher developmental stage-, tissue-, and cell-subtype-specificity of expression, and are generally less abundant in a population of cells. Despite the progress in single-cell-focused research, the origins of low population-level expression of lncRNAs in homogeneous populations of cells are poorly understood. Here, we identify HIPSTR (Heterogeneously expressed from the Intronic Plus Strand of the TFAP2A-locus RNA), a novel lncRNA gene in the developmentally regulated TFAP2A locus. HIPSTR has evolutionarily conserved expression patterns, its promoter is most active in undifferentiated cells, and depletion of HIPSTR in HEK293 and in pluripotent H1_BP cells predominantly affects the genes involved in early organismal development and cell differentiation. Most importantly, we find that HIPSTR is specifically induced and heterogeneously expressed in the 8-cell-stage human embryos during the major wave of embryonic genome activation. We systematically explore the phenomenon of cell-to-cell variation of gene expression and link it to low population-level expression of lncRNAs, showing that, similar to HIPSTR, the expression of thousands of lncRNAs is more highly heterogeneous than the expression of mRNAs in the individual, otherwise indistinguishable cells of totipotent human embryos, primordial germ cells, and stable cell lines.

Mesenchymal stromal cells (MSCs) orchestrate tissue repair by releasing cell-derived microvesicles (MVs), that presumably by small RNA species, modulate global gene expression. The knowledge of miRNA/mRNA signatures linked to a reparative status may elucidate some of the molecular events associated with MSC protection. Here, we used a model of cisplatin-induced kidney injury (AKI) to assess how MSCs or MVs could restore tissue function. MSCs and MVs presented similar protective effects, which were evidenced in vivo and in vitro by modulating apoptosis, inflammation, oxidative stress and a set of pro-survival molecules. In addition, we observed that miRNAs (i.e., miR-880, miR-141, miR-377 and miR-21) were modulated, showing active participation on regenerative process. Subsequently, we identified that MSC regulates a particular miRNA subset whose mRNA targets are associated with Wnt/TGF-β, fibrosis and epithelial-mesenchymal transition signaling pathways. Our results suggest that MSCs release MVs that transcriptionally reprogram injured cells, modulating a specific miRNA-mRNA network.

Schistosomiasis is a parasitic disease infecting hundreds of millions of people worldwide. Treatment depends on a single drug, praziquantel, which kills the Schistosoma spp. parasite only at the adult stage. HDAC inhibitors (HDACi) such as Trichostatin A (TSA) induce parasite mortality in vitro (schistosomula and adult worms), however the downstream effects of histone hyperacetylation on the parasite are not known. TSA treatment of adult worms in vitro increased histone acetylation at H3K9ac and H3K14ac, which are transcription activation marks, not affecting the unrelated transcription repression mark H3K27me3. We investigated the effect of TSA HDACi on schistosomula gene expression at three different time points, finding a marked genome-wide change in the transcriptome profile. Gene transcription activity was correlated with changes on the chromatin acetylation mark at gene promoter regions. Moreover, combining expression data with ChIP-Seq public data for schistosomula, we found that differentially expressed genes having the H3K4me3 mark at their promoter region in general showed transcription activation upon HDACi treatment, compared with those without the mark, which showed transcription down-regulation. Affected genes are enriched for DNA replication processes, most of them being up-regulated. Twenty out of 22 genes encoding proteins involved in reducing reactive oxygen species accumulation were down-regulated. Dozens of genes encoding proteins with histone reader motifs were changed, including SmEED from the PRC2 complex. We targeted SmEZH2 methyltransferase PRC2 component with a new EZH2 inhibitor (GSK343) and showed a synergistic effect with TSA, significantly increasing schistosomula mortality. Genome-wide gene expression analyses have identified important pathways and cellular functions that were affected and may explain the schistosomicidal effect of TSA HDACi. The change in expression of dozens of histone reader genes involved in regulation of the epigenetic program in S. mansoni can be used as a starting point to look for possible novel schistosomicidal targets. Human schistosomiasis is a disease caused by the parasite Schistosoma spp. that affects over 230 million people worldwide. Treatment depends on a single drug, praziquantel, and the search for new drugs calls for exploiting strategies that are successful for other pathologies such as cancer, including the test of inhibitors targeting chromatin enzymes responsible for modifying histone proteins associated with DNA. Histone modifications regulate cellular gene expression. Inhibitors targeting an important class of these histone-modifying enzymes, namely Histone Deacetylases (HDACs), are known to induce in vitro mortality of the parasite (at the schistosomula and adult worm stages), however the molecular changes caused in the parasite were not known. In this scenario, we studied the effect of the HDAC inhibitor Trichostatin A on the parasite genome-wide gene expression, on histone modifications at gene promoter regions and on the chromatin acetylation status, and found important affected gene pathways. In addition, this approach showed affected genes associated with other histone modifications, which led us to test and identify a synergistic schistosomicidal agent, GSK343, an EZH2 histone methyltransferase inhibitor. Our work points to the class of histone methyltransferase modifying enzyme as a novel drug target to be explored in the future for parasitosis treatment.

Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone. Schistosomiasis causes severe health problems in endemic areas of Africa, Southeast Asia, and Central and South America. Praziquantel is the drug of choice for treatment of at-risk populations; however, evolution of resistant worms under repeated treatment is of great concern. Combining praziquantel with another drug could not only increase efficacy of praziquantel, but also eventually hamper development of drug resistance. Our study reports the global praziquantel-induced transcriptional changes of Schistosoma mansoni adult worms in vitro, in the context of the mature female mating status (paired or unpaired). We identified sets of genes that were differentially affected in paired or unpaired mature females; we also identified genes that were similarly affected in males and females. Aiming to find possible new candidates to be tested as synergistic drugs, we used functional analysis of gene interaction networks to identify parasite genes whose expression was affected by praziquantel, and encode proteins whose human homologs are targets of different drugs already used to treat other diseases. This analysis suggested omeprazole, a widely prescribed drug, as a potential partner for praziquantel in a combination treatment. Finally, we demonstrated that this praziquantel-omeprazole combination resulted in increased worm lethality in vitro when compared with praziquantel or omeprazole alone.