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Parasitology Research Jul 2020Schistosoma is the causative agent of schistosomiasis, a common infectious disease distributed worldwide. Our previous phosphoproteomic analysis suggested that glycogen...
Schistosoma is the causative agent of schistosomiasis, a common infectious disease distributed worldwide. Our previous phosphoproteomic analysis suggested that glycogen synthase kinase 3 (GSK3), a conserved protein kinase in eukaryotes, is likely involved in protein phosphorylation of Schistosoma japonicum. Here, we aimed to identify the interacting partners of S. japonicum GSK3β (SjGSK3β) and to evaluate its role in parasite survival. Toward these ends, we determined the transcription levels of SjGSK3β at different developmental stages and identified its interacting partners of SjGSK3β by screening a yeast two-hybrid S. japonicum cDNA library. We further used RNA interference (RNAi) to inhibit the expression of SjGSK3β in adult worms in vitro and examined the resultant changes in transcription of its putative interacting proteins and in worm viability compared with those of control worms. Reverse transcription-quantitative polymerase chain analysis indicated that SjGSK3β is expressed throughout the life cycle of S. japonicum, with higher expression levels detected in the eggs and relatively higher expression level found in male worms than in female worms. By screening the yeast two-hybrid library, eight proteins were identified as potentially interacting with SjGSK3β including cell division cycle 37 homolog (Cdc37), 14-3-3 protein, tegument antigen (I(H)A), V-ATPase proteolipid subunit, myosin alkali light chain 1, and three proteins without recognized functional domains. In addition, SjGSK3β RNAi reduced the SjGSK3β gene transcript level, leading to a significant decrease in kinase activity, cell viability, and worm survival. Collectively, these findings suggested that SjGSK3β may interact with its partner proteins to influence worm survival by regulating kinase activity.
Topics: Animals; Female; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta; Helminth Proteins; Male; Protein Binding; RNA Interference; Schistosoma japonicum; Survival Analysis; Two-Hybrid System Techniques
PubMed: 32500370
DOI: 10.1007/s00436-020-06731-2 -
Acta Biochimica Et Biophysica Sinica Sep 2022Egg granuloma formation in the liver is the main pathological lesion caused by infection, which generally results in liver fibrosis and may lead to death in advanced...
Egg granuloma formation in the liver is the main pathological lesion caused by infection, which generally results in liver fibrosis and may lead to death in advanced patients. MicroRNAs (miRNAs) regulate the process of liver fibrosis, but the putative function of miRNAs in liver fibrosis induced by . infection is largely unclear. Here, we detect a new miRNA, miR-182-5p, which shows significantly decreased expression in mouse livers after stimulation by soluble egg antigen (SEA) of . or . infection. Knockdown or overexpression of miR-182-5p causes the increased or decreased expression of tristetraprolin (TTP), an important immunosuppressive protein in the process of liver fibrosis. Furthermore, knockdown of miR-182-5p upregulates TTP expression and significantly alleviates . -induced hepatic fibrosis. Our data demonstrate that downregulation of miR-182-5p increases the expression of TTP in mouse livers following schistosome infection, which leads to destabilization of inflammatory factor mRNAs and attenuates liver fibrosis. Our results uncover fine-tuning of liver inflammatory reactions related to liver fibrosis caused by . infection and provide new insights into the regulation of schistosomiasis-induced hepatic fibrosis.
Topics: Animals; Mice; Schistosoma japonicum; Tristetraprolin; Liver Cirrhosis; Liver; MicroRNAs
PubMed: 36148947
DOI: 10.3724/abbs.2022130 -
PLoS Neglected Tropical Diseases Oct 2022Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune responses against Schistosoma japonicum (S. japonicum) infection....
Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune responses against Schistosoma japonicum (S. japonicum) infection. However, the role of Toll-like receptor 7 (TLR7) in the mouse lung during S. japonicum infection and the myeloid-derived suppressor cells (MDSCs) affected by the absence of TLR7 are not clearly understood. In this study, the results indicated that the MDSCs were accumulated and the proportion and activation of CD4+ and CD8+ T cells were decreased in the lung of mice at 6-7 weeks after S. japonicum infection. Then, the expression of TLR7 was detected in isolated pulmonary MDSCs and the results showed that the expression of TLR7 in MDSCs was increased after infection. Furthermore, TLR7 agonist R848 could down-regulate the induction effect of the soluble egg antigen (SEA) on pulmonary MDSCs in vitro. Meanwhile, TLR7 deficiency could promote the pulmonary MDSCs expansion and function by up-regulating the expression of PD-L1/2 and secreting of IL-10 in the mice infected with S. japonicum. Mechanistic studies revealed that S. japonicum infection and the antigen effects are mediated by NF-κB signaling. Moreover, TLR7 deficiency aggravates S. japonicum infection-induced damage in the lung, with more inflammatory cells infiltration, interstitial dilatation and granuloma in the tissue. In summary, this study indicated that TLR7 signaling inhibits the accumulation and function of MDSCs in S. japonicum infected mouse lung by down-regulating the expression of PD-L1/2 and secreting of IL-10, via NF-κB signaling.
Topics: Animals; Mice; B7-H1 Antigen; Interleukin-10; Lung; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; NF-kappa B; Schistosoma japonicum; Schistosomiasis japonica; Toll-Like Receptor 7
PubMed: 36279265
DOI: 10.1371/journal.pntd.0010851 -
Experimental Parasitology May 2023Schistosomiasis is an important zoonotic disease affecting up to 40 kinds of animals and is responsible for ∼250 million human cases per year. Due to the extensive use...
Schistosomiasis is an important zoonotic disease affecting up to 40 kinds of animals and is responsible for ∼250 million human cases per year. Due to the extensive use of praziquantel for the treatment of parasitic diseases, drug resistance has been reported. Consequently, novel drugs and effective vaccines are urgently needed for sustained control of schistosomiasis. Targeting reproductive development of Schistosoma japonicum could contribute to the control of schistosomiasis. In this study, five highly expressed proteins (S. japonicum large subunit ribosomal protein L7e, S. japonicum glutathione S-transferase class-mu 26 kDa isozyme, S. japonicum UDP-galactose-4-epimerase and two hypothetical proteins SjCAX70849 and SjCAX72486) in 18, 21, 23, and 25-day mature female worms compared to single-sex infected female worms were selected based on our previous proteomic analysis. Quantitative real-time polymerase chain reaction analysis and long-term interference with small interfering RNA were performed to identify the biological functions of these five proteins. The transcriptional profiles suggested that all five proteins participated in the maturation of S. japonicum. RNA interference against these proteins resulted in morphological changes to S. japonicum. The results of an immunoprotection assay revealed that immunization of mice with recombinant SjUL-30 and SjCAX72486 upregulated production of immunoglobulin G-specific antibodies. Collectively, the results demonstrated that these five differentially expressed proteins were vital to reproduction of S. japonicum and, thus, are potential candidate antigens for immune protection against schistosomiasis.
Topics: Female; Humans; Animals; Mice; Schistosoma japonicum; Proteomics; Schistosomiasis; Praziquantel; Sexual and Gender Minorities; Schistosomiasis japonica
PubMed: 36914063
DOI: 10.1016/j.exppara.2023.108504 -
Parasites & Vectors Oct 2021Schistosomiasis is a debilitating and neglected tropical disease for which praziquantel (PZQ) remains the first-choice drug for treatment and control of the disease. In...
BACKGROUND
Schistosomiasis is a debilitating and neglected tropical disease for which praziquantel (PZQ) remains the first-choice drug for treatment and control of the disease. In our previous studies, we found that the patented compound DW-3-15 (patent no. ZL201110142538.2) displayed significant and stabilized antiparasitic activity through a mechanism that might be distinct from PZQ. Here, we investigated the antischistosomal efficacy of PZQ combined with DW-3-15 against schistosomula and adult worms of Schistosoma japonicum in vitro and in vivo, to verify whether there was a synergistic effect of the two compounds.
METHODS
The antischistosomal efficacy of PZQ combined with DW-3-15 in comparison with an untreated control and monotherapy group against schistosomula and adult worms was assessed both in vitro and in vivo. Parasitological studies, scanning electron microscopy, combination index, and histopathological analysis were used for the assessment.
RESULTS
The results showed significantly reduced viability of schistosomes, achieving 100% viability reduction for juveniles and males by combination chemotherapy using PZQ together with DW-3-15 in vitro. The combination index was 0.28, 0.27, and 0.53 at the higher concentration of PZQ combined with DW-3-15 against juveniles, males, and females, respectively, indicating that the two compounds display strong synergism. Scanning electron microscopy observations also demonstrated that the compound combination induced more severe and extensive alterations to the tegument and subtegument of S. japonicum than those with each compound alone. In vivo, compared with the single-compound-treated group, the group treated with the higher-dose combination demonstrated the best schistosomicidal efficacy, with significantly reduced worm burden, egg burden, and granuloma count and area, which was evident against schistosomula and adult worms.
CONCLUSIONS
Our study provides a potential novel chemotherapy for schistosomiasis caused by S. japonicum. It would improve the antischistosomal effect on schistosomula and adult worms of S. japonicum, and decrease individual dosages.
Topics: Animals; Drug Synergism; Drug Therapy, Combination; Female; Mice, Inbred ICR; Parasite Egg Count; Praziquantel; Schistosoma japonicum; Schistosomicides; Mice
PubMed: 34702326
DOI: 10.1186/s13071-021-05065-x -
Parasitology Research Jan 2015Among the three main schistosomes (Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haematobium) known to infect humans, S. japonicum causes the most serious... (Review)
Review
Among the three main schistosomes (Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haematobium) known to infect humans, S. japonicum causes the most serious pathological lesions. In China, only schistosomiasis japonica is transmitted. From the 1950s, massive epidemiological investigations and active control measures for schistosomiasis japonica have been carried out. At the early stage of schistosomiasis control program, there were about 12 million schistosomiasis patients, and about 5% of schistosomiasis patients belong to advanced patients, which was 600,000. After more than a half century of active schistosomiasis control work, the schistosomiasis situation has been reduced markedly. The nearest epidemiological investigation showed that, by the end of 2012, there were still 240,000 schistosomiasis patients with the descent rate of 98% and 30,000 advanced patients with the descent rate of 95%. This paper reviews the rich experiences of advanced schistosomiasis research and control in China, including that the epidemiology researches confirm there is a family aggregation of advanced schistosomiasis and advanced schistosomiasis patients have no significance to the schistosomiasis transmission in transmission-interrupted areas but still are an infection source in endemic areas; pathogenic mechanism researches verify that genetic factors and immunoregulation play important roles in the disease developing process; ultrasound image examinations are used not only in the diagnosis and differential diagnosis of advanced schistosomiasis but also in the guidance of treatment and evaluation of therapeutic effects and, furthermore, in the risk predictions of portal hypertension and upper gastrointestinal hemorrhage; clinical practices demonstrate that praziquantel can be used in most of advanced schistosomiasis patients, and the therapy not only can interrupt the schistosomiasis transmission somewhat but also is favorable for liver fibrosis improvement; the ascetic fluid concentration afflux is used in the therapy for obstinate ascites, and endoscopic varices ligation is used in the treatment of upper gastrointestinal bleeding, and both have good effects; hundreds and thousands of severe splenomegaly advanced schistosomiasis patients received splenectomy, and the long-term survival rate is more than 90%, most of them are basically cured from the disease and their labor force recovers, some dwarf patients begin growing and developing again, and some sterile women became fertile; the researches of traditional Chinese medicine in the treatment of liver fibrosis have made progress, such as Cordyceps sinensis showing some anti-fibrosis effect in the animal experiments and primary clinical trials; the animal experiments and epidemiological investigations indicate that schistosome infection is one of the carcinogenesis risk factors, especially for liver cancer. In conclusion, these experiences and lessons are plentiful and worth sharing with the peers of other endemic countries for reference.
Topics: Animals; Anthelmintics; China; Humans; Liver Cirrhosis; Praziquantel; Schistosoma japonicum; Schistosomiasis japonica; Splenomegaly
PubMed: 25403379
DOI: 10.1007/s00436-014-4225-x -
International Journal For Parasitology Oct 2021Schistosomiasis is caused by dioecious helminths of the genus Schistosoma. Recent work indicated that unpaired female and male schistosomes can survive within their...
Schistosomiasis is caused by dioecious helminths of the genus Schistosoma. Recent work indicated that unpaired female and male schistosomes can survive within their definitive host for at least 1 year, although the viability or fertility of these worms after subsequent pairing remained untested. We performed two experiments on laboratory mice, one with female Schistosoma japonicum exposure first and male schistosomes second and another vice versa. After surviving as single-sex unpaired forms for up to 1 year, 58.5% of male and 70% of female schistosomes were able to mate and produce viable eggs. This highlights an additional biological challenge in achieving elimination of schistosomiasis.
Topics: Animals; Female; Fertility; Male; Mice; Reproduction; Schistosoma japonicum; Schistosomiasis; Schistosomiasis japonica
PubMed: 33905765
DOI: 10.1016/j.ijpara.2021.03.005 -
International Journal For Parasitology Aug 2022Circular RNAs (circRNAs) are a class of novel, widespread, covalently closed RNAs that have played an essential role in animal gene regulation. To systematically explore...
Circular RNAs (circRNAs) are a class of novel, widespread, covalently closed RNAs that have played an essential role in animal gene regulation. To systematically explore circRNAs in the blood fluke Schistosoma japonicum, we performed RNA sequencing and bioinformatics analysis, and found that hundreds of circRNAs showed gender-associated expression. Among these identified circRNAs, more than 77.54% and 74.73% were putatively derived from the exon region of the genome and some circRNAs showed gender-associated expressions. The functional prediction of circRNAs (circ_003826 and circ_004690) showed potential binding sites and possibly acted as the sponge to regulate microRNAs (miRNAs) sja-miR-1, sja-miR-133 and sja-miR-3504. Altogether, these findings demonstrated that S. japonicum also contains circRNAs, which may have potential regulatory roles during schistosome development.
Topics: Animals; Genome; MicroRNAs; RNA, Circular; Schistosoma japonicum; Sequence Analysis, RNA
PubMed: 35810786
DOI: 10.1016/j.ijpara.2022.05.003 -
Immunology Sep 2016Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells...
Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells depends on both the nature of the activating stimulus and the local microenvironment (e.g. cytokines and other soluble factors). In the present study, we found an accumulation of large numbers of IFN-γ(+) IL-4(+) CD4(+) T cells in mouse livers. This IFN-γ(+) IL-4(+) cell population increased from 0·68 ± 0·57% in uninfected mice to 7·05 ± 3·0% by week 4 following infection and to 9·6 ± 5·28% by week 6, before decreasing to 6·3 ± 5·9% by week 8 in CD4 T cells. Moreover, IFN-γ(+) IL-4(+) Th cells were also found in mouse spleen and mesenteric lymph nodes 6 weeks after infection. The majority of the IFN-γ(+) IL-4(+) Th cells were thought to be related to a state of immune activation, and some were memory T cells. Moreover, we found that these S. japonicum infection-induced IFN-γ(+) IL-4(+) cells could express interleukin-2 (IL-2), IL-9, IL-17 and high IL-10 levels at 6 weeks after S. japonicum infection. Taken together, our data suggest the existence of a population of IFN-γ(+) IL-4(+) plasticity effector/memory Th cells following S. japonicum infection in C57BL/6 mice.
Topics: Animals; Cell Differentiation; Cells, Cultured; Female; Immunologic Memory; Interferon-gamma; Interleukin-4; Liver; Mice; Mice, Inbred C57BL; Schistosoma japonicum; Schistosomiasis japonica; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Th1-Th2 Balance
PubMed: 27242265
DOI: 10.1111/imm.12623 -
Biomedicine & Pharmacotherapy =... May 2022Triggering receptor expressed on myeloid cells 1 (TREM-1) is a transmembrane glycoprotein receptor and TREM-1 expression reached the peak at 6 weeks after infection with...
Triggering receptor expressed on myeloid cells 1 (TREM-1) is a transmembrane glycoprotein receptor and TREM-1 expression reached the peak at 6 weeks after infection with Schistosoma japonicum and inhibited subsequently. Since TREM-1 may be involved in the macrophage polarization process, the reason for the inhibition of TREM-1 expression in chronic schistosomiasis engaged us in them. In this study, flow cytometry was used to observe TREM-1 expression in peritoneal macrophages from mice infected with Schistosoma japonicum. Since P40 is one of the main components from schistosoma eggs, western blot and dual-luciferase reporter assays were performed to observe the effect of recombinant Schistosoma japonicum P40 protein (rSjP40) on TREM-1 expression in the mouse leukemic monocyte/macrophage cell line RAW264.7. These methods were also conducted to observe the effect of FOXO3a on the expression of TREM-1 in RAW264.7 cells, and a ChIP assay was performed to confirm the binding site of FOXO3a to the TREM-1 promoter. Our results showed that TREM-1 expression reached the peak in peritoneal macrophages from mice at 6 weeks after infection with Schistosoma japonicum. rSjP40 inhibited TREM-1 promoter activity at the position of - 1924 ~ - 1531 bp. rSjP40 down-regulated TREM-1 and FOXO3a protein expression in RAW264.7 cells. TREM-1 protein expression may be regulated by binding of FOXO3a to the promoter of TREM-1 in RAW264.7 cells. In conclusion, we found that rSjP40 inhibited TREM-1 expression in macrophages by inhibiting FOXO3a expression. This study will provide the basis for the study to explore the role of TREM-1 in Schistosoma japonicum infection.
Topics: Animals; Macrophages; Mice; Recombinant Proteins; Schistosoma japonicum; Schistosomiasis japonica; Triggering Receptor Expressed on Myeloid Cells-1
PubMed: 35306429
DOI: 10.1016/j.biopha.2022.112826