Smp38 MAP Kinase Regulation in Schistosoma mansoni: Roles in Survival, Oviposition, and Protection Against Oxidative Stress

Avelar, Lívia; Gava, Sandra Grossi; Neves, Renata Heisler; Silva, Mercedes Carolina Soares; Araújo, Neusa; Tavares, Naiara Clemente; Khal, Assmaa El; Mattos, Ana Carolina Alves de; Machado-Silva, José Roberto; Oliveira, Guilherme; Mourão, Marina Moraes

doi:10.3389/fimmu.2019.00021

Cited by 29 publications

(34 citation statements)

References 71 publications

(83 reference statements)

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“…Schistosoma mansoni cercariae were obtained by exposing infected Biomphalaria glabrata snails to light for 1-2 hours to induce shedding. For RNAi assays, and western blotting analysis, cercariae were mechanically transformed into schistosomula of cercariae [18] and were cultured in Glasgow Mem (GMEM) (Sigma-Aldrich, Germany) supplemented as previously described [19]. Infected mice were perfused and adult worms were recovered from the hepatic portal system, while the livers of the same animals were removed for egg recovery.…”

Section: Methodsmentioning

confidence: 99%

Sm16, ASchistosoma mansoniImmunomodulatory Protein, Fails to Elicit a Protective Immune Response and Does Not Have an Essential Role in Parasite Survival in the Definitive Host

Bernardes¹,

Araújo²,

Carvalho³

et al. 2019

Journal of Immunology Research

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Sm16 is an immunomodulatory protein that seems to play a key role in the suppression of the cutaneous inflammatory response during Schistosoma mansoni penetration of the skin of definitive hosts. Therefore, Sm16 represents a potential target for protective immune responses induced by vaccination. In this work, we generated the recombinant protein rSm16 and produced polyclonal antibodies against this protein to evaluate its expression during different parasite life-cycle stages and its location on the surface of the parasite. In addition, we analyzed the immune responses elicited by immunization with rSm16 using two different vaccine formulations, as well as its ability to induce protection in Balb/c mice. In order to explore the biological function of Sm16 during the course of experimental infection, RNA interference was also employed. Our results demonstrated that Sm16 is expressed in cercaria and schistosomula and is located in the schistosomula surface. Despite humoral and cellular immune responses triggered by vaccination using rSm16 associated with either Freund's or alum adjuvants, immunized mice presented no reduction in either parasite burden or parasite egg laying. Knockdown of Sm16 gene expression in schistosomula resulted in decreased parasite size in vitro but had no effect on parasite survival or egg production in vivo. Thus, our findings demonstrate that although the vaccine formulations used in this study succeeded in activating immune responses, these failed to promote parasite elimination. Finally, we have shown that Sm16 is not vital for parasite survival in the definitive host and hence may not represent a suitable target for vaccine development.

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Section: Methodsmentioning

confidence: 99%

Sm16, ASchistosoma mansoniImmunomodulatory Protein, Fails to Elicit a Protective Immune Response and Does Not Have an Essential Role in Parasite Survival in the Definitive Host

Bernardes¹,

Araújo²,

Carvalho³

et al. 2019

Journal of Immunology Research

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“…Since the JNK and p38 MAPK signaling pathways are triggered by multiple stimuli that simultaneously activate both pathways and consequently share several upstream regulators (Wagner and Nebreda, 2009), we compared the DEGs found here with those found for Smp38 knocked-down schistosomula (Avelar et al, 2019). The SmJNK and Smp38 MAPK pathways in S. mansoni presented an intersection of 311 and 89 genes with decreased and increased expression, respectively ( Figure 6 ).…”

Section: Resultsmentioning

confidence: 99%

“…We also compared DEGs of schistosomula SmJNK knocked-down with those found in schistosomula Smp38 knocked-down (Avelar et al, 2019). The down-regulated DEGs that overlap in both datasets were subjected to the BioMart tool () from WormBase ParaSite (Howe et al, 2017) to search for orthologs in the nematode Caenorhabditis elegans.…”

Section: Methodsmentioning

confidence: 99%

“…Also, we elucidated genes that are target of regulation by SmJNK knockdown, aiming to identify novel parasite-specific targets in addition to contributing to a better understanding of this signaling pathway. Additionally, we checked for a crosstalk between SmJNK pathway and the previously reported data from Smp38 (Avelar et al, 2019). Finally, we identified specific targets that correlate with previously observed phenotypes of developmental impairment (Andrade et al, 2014; Avelar et al, 2019) which is highly desirable for the design of new anti-schistosome drugs.…”

Section: Introductionmentioning

confidence: 99%

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Profiling Transcriptional Regulation and Functional Roles of Schistosoma mansoni c-Jun N-Terminal Kinase

et al. 2019

Self Cite

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Mitogen-activated protein kinases (MAPKs) play a regulatory role and influence various biological activities, such as cell proliferation, differentiation, and survival. Our group has demonstrated through functional studies that Schistosoma mansoni c-Jun N-terminal kinase (SmJNK) MAPK is involved in the parasite’s development, reproduction, and survival. SmJNK can, therefore, be considered a potential target for the development of new drugs. Considering the importance of SmJNK in S. mansoni maturation, we aimed at understanding of SmJNK regulated signaling pathways in the parasite, correlating expression data with S. mansoni development. To better understand the role of SmJNK in S. mansoni intravertebrate host life stages, RNA interference knockdown was performed in adult worms and in schistosomula larval stage. SmJNK knocked-down in adult worms showed a decrease in oviposition and no significant alteration in their movement. RNASeq libraries of SmJNK knockdown schistosomula were sequenced. A total of 495 differentially expressed genes were observed in the SmJNK knockdown parasites, of which 373 were down-regulated and 122 up-regulated. Among the down-regulated genes, we found transcripts related to protein folding, purine nucleotide metabolism, the structural composition of ribosomes and cytoskeleton. Genes coding for proteins that bind to nucleic acids and proteins involved in the phagosome and spliceosome pathways were enriched. Additionally, we found that SmJNK and Smp38 MAPK signaling pathways converge regulating the expression of a large set of genes. C. elegans orthologous genes were enriched for genes related to sterility and oocyte maturation, corroborating the observed phenotype alteration. This work allowed an in-depth analysis of the SmJNK signaling pathway, elucidating gene targets of regulation and functional roles of this critical kinase for parasite maturation.

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“…Ct values are shown in Supplementary Table S9. Real-time qPCR data were normalized in relation to the level of expression of two reference genes previously used in the literature, namely Smp_900000 [120][121][122] www.nature.com/scientificreports/ tions, using the online https ://statt rek.com/onlin e-calcu lator /hyper geome tric.aspx tool. Quantification of data are represented as mean ± SEM and p value thresholds were * < 0.05, ** < 0.01, *** < 0.001 and **** < 0.0001.…”

Section: Reverse Transcription and Quantitative Pcr (Rt-qpcr) Assaysmentioning

confidence: 99%

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

Amaral

Maciel

Silveira

et al. 2020

Sci Rep

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Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects more than 200 million people worldwide. There is only one drug indicated for treatment, praziquantel, which may lead to parasite resistance emergence. The ribonucleoside analogue 5-azacytidine (5-AzaC) is an epigenetic drug that inhibits S. mansoni oviposition and ovarian development through interference with parasite transcription, translation and stem cell activities. Therefore, studying the downstream pathways affected by 5-AzaC in S. mansoni may contribute to the discovery of new drug targets. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein coding potential that have been involved in reproduction, stem cell maintenance and drug resistance. We have recently published a catalog of lncRNAs expressed in S. mansoni life-cycle stages, tissues and single cells. However, it remains largely unknown if lncRNAs are responsive to epigenetic drugs in parasites. Here, we show by RNA-Seq re-analyses that hundreds of lncRNAs are differentially expressed after in vitro 5-AzaC treatment of S. mansoni females, including intergenic, antisense and sense lncRNAs. Many of these lncRNAs belong to co-expression network modules related to male metabolism and are also differentially expressed in unpaired compared with paired females and ovaries. Half of these lncRNAs possess histone marks at their genomic loci, indicating regulation by histone modification. Among a selected set of 8 lncRNAs, half of them were validated by RT-qPCR as differentially expressed in females, and some of them also in males. Interestingly, these lncRNAs are also expressed in other life-cycle stages. This study demonstrates that many lncRNAs potentially involved with S. mansoni reproductive biology are modulated by 5-AzaC and sheds light on the relevance of exploring lncRNAs in response to drug treatments in parasites.

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Smp38 MAP Kinase Regulation in Schistosoma mansoni: Roles in Survival, Oviposition, and Protection Against Oxidative Stress

Cited by 29 publications

References 71 publications

Sm16, ASchistosoma mansoniImmunomodulatory Protein, Fails to Elicit a Protective Immune Response and Does Not Have an Essential Role in Parasite Survival in the Definitive Host

Sm16, ASchistosoma mansoniImmunomodulatory Protein, Fails to Elicit a Protective Immune Response and Does Not Have an Essential Role in Parasite Survival in the Definitive Host

Profiling Transcriptional Regulation and Functional Roles of Schistosoma mansoni c-Jun N-Terminal Kinase

Long non-coding RNA levels can be modulated by 5-azacytidine in Schistosoma mansoni

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