-
EBioMedicine Sep 2023Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic...
BACKGROUND
Regulatory T cells (Tregs) can alleviate the development of autoimmune and inflammatory diseases, thereby proposing their role as a new therapeutic strategy. Parasitic helminths have co-evolved with hosts to generate immunological privilege and immune tolerance through inducing Tregs. Thus, constructing a "Tregs-induction"-based discovery pipeline from parasitic helminth is a promising strategy to control autoimmune and inflammatory diseases.
METHODS
The gel filtration chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC) were used to isolate immunomodulatory components from the egg extracts of Schistosoma japonicum. The extracted peptides were evaluated for their effects on Tregs suppressive functions using flow cytometry, ELISA and T cell suppression assay. Finally, we carried out colitis and psoriasis models to evaluate the function of Tregs induced by helminth-derived peptide in vivo.
FINDINGS
Here, based on target-driven discovery strategy, we successfully identified a small 3 kDa peptide (SjDX5-53) from egg extracts of schistosome, which promoted both human and murine Tregs production. SjDX5-53 presented immunosuppressive function by arresting dendritic cells (DCs) at an immature state and augmenting the proportion and suppressive capacity of Tregs. In mouse models, SjDX5-53 protected mice against autoimmune-related colitis and psoriasis through inducing Tregs and inhibiting inflammatory T-helper (Th) 1 and Th17 responses.
INTERPRETATION
SjDX5-53 exhibited the promising therapeutic effects in alleviating the phenotype of immune-related colitis and psoriasis. This study displayed a screening and validation pipeline of the inducer of Tregs from helminth eggs, highlighting the discovery of new biologics inspired by co-evolution of hosts and their parasites.
FUNDING
This study was supported by the Natural Science Foundation of China (82272368) and Natural Science Foundation of Jiangsu Province (BK20211586).
Topics: Mice; Humans; Animals; Schistosoma japonicum; T-Lymphocytes, Regulatory; Autoimmune Diseases; Colitis; Psoriasis
PubMed: 37579625
DOI: 10.1016/j.ebiom.2023.104751 -
PLoS Pathogens Feb 2022Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition...
Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I-IFN-independent manner.
Topics: Animals; Female; Immunity; Interferon Regulatory Factor-3; Interferon Type I; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Schistosomiasis; Schistosomiasis japonica; Signal Transduction
PubMed: 35108342
DOI: 10.1371/journal.ppat.1010233 -
Frontiers in Veterinary Science 2021The deposition of () eggs commonly induces inflammation, fibrosis, hyperplasia, ulceration, and polyposis in the colon, which poses a serious threat to human health....
The deposition of () eggs commonly induces inflammation, fibrosis, hyperplasia, ulceration, and polyposis in the colon, which poses a serious threat to human health. However, the underlying mechanism is largely neglected. Recently, the disorder of glucose and lipid metabolism was reported to participate in the liver fibrosis induced by the parasite, which provides a novel clue for studying the underlying mechanism of the intestinal pathology of the disease. This study focused on the metabolic reprogramming profiles of glucose and lipid in the colon of mice infected by . We found that infection shortened the colonic length, impaired intestinal integrity, induced egg-granuloma formation, and increased colonic inflammation. The expression of key enzymes involved in the pathways regulating glucose and lipid metabolism was upregulated in the colon of infected mice. Conversely, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and its downstream signaling targets were significantly inhibited after infection. In line with these results, stimulation with soluble egg antigens (SEA) downregulated the expression of PTEN in CT-26 cells and induced metabolic alterations similar to that observed under results. Moreover, PTEN over-expression prevented the reprogramming of glucose and lipid metabolism induced by SEA in CT-26 cells. Overall, the present study showed that infection induces the reprogramming of glucose and lipid metabolism in the colon of mice, and PTEN may play a vital role in mediating this metabolic reprogramming. These findings provide a novel insight into the pathogenicity of in hosts.
PubMed: 33791356
DOI: 10.3389/fvets.2021.645807 -
Journal of Cellular and Molecular... Aug 2023Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of...
Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of liver granulomas and fibrosis by undergoing polarization from M1 to M2 type during schistosomiasis. Therefore, regulating macrophage polarization is important for controlling pathological changes that occur during this disease. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed on the surface of macrophages, dendritic cells and other immune cells has been shown to play a role in inhibiting inflammatory responses and regulating M2 macrophage polarization, however its role in macrophage polarization in schistosomiasis has not been investigated. In this study, we confirmed that TREM2 expression was upregulated in the livers and peritoneal macrophages of mice infected with Schistosoma japonicum. Moreover, the TREM2 expression trend correlated with the expression of M2 macrophage polarization-related molecules in the liver tissues of S. japonicum-infected mice. Using Trem2 mice, we also showed that Trem2 deletion inhibited Arg1 and Ym1 expression in liver tissues. Trem2 deletion also increased the number of F4/80 + CD86+ cells in peritoneal macrophages of infected mice. In summary, our study suggests that TREM2 may be involved in M2 macrophage polarization during schistosomiasis.
Topics: Humans; Animals; Mice; Schistosoma japonicum; Macrophages, Peritoneal; Schistosomiasis japonica; Macrophages; Liver; Schistosomiasis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37430471
DOI: 10.1111/jcmm.17842 -
Parasites & Vectors Sep 2021Harnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We...
BACKGROUND
Harnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We previously identified a small molecule peptide from Schistosoma japonicum and named it SJMHE1. SJMHE1 can suppress delayed-type hypersensitivity, collagen-induced arthritis and asthma in mice. In this study, we assessed the effects of SJMHE1 on dextran sulfate sodium (DSS)-induced acute and chronic colitis.
METHODS
Acute and chronic colitis were induced in C57BL/6 mice by DSS, following which the mice were injected with an emulsifier SJMHE1 or phosphate-buffered saline. The mice were then examined for body weight loss, disease activity index, colon length, histopathological changes, cytokine expression and helper T (Th) cell subset distribution.
RESULTS
SJMHE1 treatment significantly suppressed DSS-induced acute and chronic colitis, improved disease activity and pathological damage to the colon and modulated the expression of pro-inflammatory and anti-inflammatory cytokines in splenocytes and the colon. In addition, SJMHE1 treatment reduced the percentage of Th1 and Th17 cells and increased the percentage of Th2 and regulatory T (Treg) cells in the splenocytes and mesenteric lymph nodes of mice with acute colitis. Similarly, SJMHE1 treatment upregulated the expression of interleukin-10 (IL-10) mRNA, downregulated the expression of IL-17 mRNA and modulated the Th cell balance in mice with chronic colitis.
CONCLUSIONS
Our data show that SJMHE1 provided protection against acute and chronic colitis by restoring the immune balance. As a small molecule, SJMHE1 might be a novel agent for the treatment of IBDs without immunogenicity concerns.
Topics: Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Male; Mice; Mice, Inbred C57BL; Peptides; Schistosoma japonicum; Schistosomiasis japonica; Th1 Cells; Th17 Cells; Th2 Cells
PubMed: 34488863
DOI: 10.1186/s13071-021-04977-y -
Parasites & Vectors May 2022Schistosomiasis, an acute and chronic parasitic disease, causes substantial morbidity and mortality in tropical and subtropical regions of the world. Iron is an...
BACKGROUND
Schistosomiasis, an acute and chronic parasitic disease, causes substantial morbidity and mortality in tropical and subtropical regions of the world. Iron is an essential constituent of numerous macromolecules involving in important cellular reactions in virtually all organisms. Trematodes of the genus Schistosoma live in iron-rich blood, feed on red blood cells and store abundant iron in vitelline cells. Ferritins are multi-meric proteins that store iron inside cells. Three ferritin isoforms in Schistosoma japonicum are known, namely SjFer0, SjFer1 and SjFer2; however, their impact on the growth and development of the parasites is still unknown. In this study we report on and characterize the ferritins in S. japonicum.
METHODS
A phylogenetic tree of the SjFer0, SjFer1 and SjFer2 genes was constructed to show the evolutionary relationship among species of genus Schistosoma. RNA interference in vivo was used to investigate the impact of SjFer0 on schistosome growth and development. Immunofluorescence assay was applied to localize the expression of the ferritins. RNA-sequencing was performed to characterize the iron transport profile after RNA interference.
RESULTS
SjFer0 was found to have low similarity with SjFer1 and SjFer2 and contain an additional signal peptide sequence. Phylogenetic analysis revealed that SjFer0 can only cluster with some ferritins of other trematodes and tapeworms, suggesting that this ferritin branch might be unique to these parasites. RNA interference in vivo showed that SjFer0 significantly affected the growth and development of schistosomula but did not affect egg production of adult female worms. SjFer1 and SjFer2 had no significant impact on growth and development. The immunofluorescence study showed that SjFer0 was widely expressed in the somatic cells and vitelline glands but not in the testicle or ovary. RNA-sequencing indicated that, in female, the ion transport process and calcium ion binding function were downregulated after SjFer0 RNA interference. Among the differentially downregulated genes, Sj-cpi-2, annexin and insulin-like growth factor-binding protein may be accounted for the suppression of schistosome growth and development.
CONCLUSIONS
The results indicate that SjFer0 affects the growth and development of schistosomula but does not affect egg production of adult female worms. SjFer0 can rescue the growth of the fet3fet4 double mutant Saccharomyces cerevisiae (strain DEY1453), suggesting being able to promote iron absorption. The RNA interference of SjFer0 inferred that the suppression of worm growth and development may via down-regulating Sj-cpi-2, annexin, and IGFBP.
Topics: Animals; Annexins; Female; Ferritins; Growth and Development; Iron; Phylogeny; RNA; Schistosoma japonicum; Schistosomiasis japonica
PubMed: 35610663
DOI: 10.1186/s13071-022-05247-1 -
Journal of Parasitic Diseases :... Sep 2021Schistosomiasis is a parasitic disease caused by blood flukes of the genus and involves bovines and snails as a reservoir and intermediate hosts, respectively. This...
Schistosomiasis is a parasitic disease caused by blood flukes of the genus and involves bovines and snails as a reservoir and intermediate hosts, respectively. This disease is endemic in Lake Mainit, Philippines, as early as 1947. The study was conducted to determine the prevalence of infection in ricefields adjacent to Lake Mainit by collecting snails and bovine fecal samples which are then subjected to laboratory examination and analysis. A total of 345 individuals and 32 bovine fecal samples were collected from six barangay rice field stations adjacent to Lake Mainit from February and July 2020 Among the six barangays, Alipao had the highest prevalence of in (39.71%), followed by San Isidro (28.3%), Matin-ao (18%), Poblacion (15%), and Magpayang (2.5%). No snails were collected in the ricefields of Cuyago. had an overall prevalence of 14.71% in all the bovines sampled, where Cuyago had the highest prevalence (50.0%) followed by Alipao (33.33%). The intensity of infection of eggs per gram (MPEG = 0.70) among bovines is categorized as light. Bovine contamination index calculations revealed that, on average, infected bovines in Lake Mainit excrete ~ 55,000 eggs per day. The study confirms the important role of bovines as a reservoir host for schistosomiasis. The presence of both infected bovines and in ricefields makes this agricultural venue an important nidus of emergence in Lake Mainit. An integrated approach of mass drug administration (MDA) of praziquantel, implementation of a bovine vaccine-directed control program, and providing farmers with mechanized farm equipment are highly recommended to minimize the risk of exposure and infection to schistosomiasis in rice fields adjacent to the lake.
PubMed: 33746379
DOI: 10.1007/s12639-021-01372-3 -
Frontiers in Cellular and Infection... 2022The microRNA-124-3p plays an important role in regulating development and neurogenesis. Previous microRNA sequencing analyses of revealed sja-miR-124-3p differential...
The microRNA-124-3p plays an important role in regulating development and neurogenesis. Previous microRNA sequencing analyses of revealed sja-miR-124-3p differential expression patterns in schistosomes from different hosts and at different developmental stages. This study explores the regulatory role of sja-miR-124-3p in development and reproduction. Quantitative reverse-transcription PCR (qRT-PCR) showed that the expression level of sja-miR-124-3p in from resistant hosts, such as , and unsuitable hosts, such as rats and water buffalo, was significantly higher than that in mice and yellow cattle at the same developmental stage. Overexpressing sja-miR-124-3p in infected mice led to a hepatic egg reduction rate of 36.97%, smaller egg granulomas in the livers, increased liver weight, subsided hepatocyte necrosis, and diminished inflammatory cell infiltration. The width of female worms increased but decreased in males. The vitelline cells were irregular, swollen, or fused. The teguments and ventral sucker of males and females were swollen and broken, but the morphological changes were particularly notable in males. qRT-PCR and dual-luciferase reporter assay system were used to confirm the -predicted target genes, DEAD-box ATP-dependent RNA helicase 1 () and DNA polymerase II subunit 2 (). Our results showed that RNA interference (RNAi)-mediated silencing in mice provided a 24.55% worm reduction rate and an 18.36% egg reduction rate, but the difference was not significant ( > 0.05). Thus, our findings suggest that sja-miR-124-3p has an important role in growth, development, and reproduction in . All these results will greatly contribute toward providing important clues for searching vaccine candidates and new drug targets against schistosomiasis.
Topics: Animals; Cattle; Female; Liver; Male; Mice; MicroRNAs; RNA Interference; Rats; Reproduction; Schistosoma japonicum
PubMed: 35493736
DOI: 10.3389/fcimb.2022.862496 -
Acta Tropica Aug 2022The co-evolution of Schistosoma and its host necessitates the use of extracellular vesicles (EVs) generated by different lifecycle stages to manipulate the host immune... (Review)
Review
The co-evolution of Schistosoma and its host necessitates the use of extracellular vesicles (EVs) generated by different lifecycle stages to manipulate the host immune system to achieve a delicate balance between the survival of the parasite and the limited pathology of the host. EVs are phospholipid bilayer membrane-enclosed vesicles capable of transferring a complex mixture of proteins, lipids, and genetic materials to the host. They are nano-scale-sized vesicles involved in cellular communication. In this review, the author summarized the proteins involved in the biogenesis of schistosome-derived EVs and their cargo load. miRNAs are one cargo molecule that can underpin EVs functions and significantly affect parasite/host interactions and immune modulation. They skew macrophage polarization towards the M1 phenotype and downregulate Th2 immunity. Schistosoma can evade the host immune system's harmful effects by utilizing this strategy. In order to compromise the protective effect of Th2, EVs upregulate T regulatory cells and activate eosinophils, which contribute to granuloma formation. Schistosomal EVs also affect fibrosis by acting on non-immune cells such as hepatic stellate cells. These vesicles drew attention to translational applications in diagnosis, immunotherapy, and potential vaccines. A deep understanding of the interaction of schistosome-derived EVs with host cells will significantly increase our knowledge about the dynamics between the host and the worm that may aid in controlling this debilitating disease.
Topics: Animals; Extracellular Vesicles; Host-Parasite Interactions; MicroRNAs; Proteomics; Schistosoma japonicum
PubMed: 35427535
DOI: 10.1016/j.actatropica.2022.106467 -
Parasites & Vectors Nov 2022Schistosoma japonicum infection is an important public health problem, imposing heavy social and economic burdens in 78 countries worldwide. However, the mechanism of...
BACKGROUND
Schistosoma japonicum infection is an important public health problem, imposing heavy social and economic burdens in 78 countries worldwide. However, the mechanism of transition from chronic to advanced S. japonicum infection remains largely unknown. Evidences suggested that gut microbiota plays a role in the pathogenesis of S. japonicum infection. However, the composition of the gut microbiota in patients with chronic and advanced S. japonicum infection is not well defined. In this study, we compared the composition of the intestinal flora in patients with chronic and advanced S. japonicum infection.
METHODS
The feces of 24 patients with chronic S. japonicum infection and five patients with advanced S. japonicum infection from the same area were collected according to standard procedures, and 16S rRNA sequencing technology was used to analyze the intestinal microbial composition of the two groups of patients.
RESULTS
We found that alteration occurs in the gut microbiota between the groups of patients with chronic and advanced S. japonicum infections. Analysis of alpha and beta diversity indicated that the diversity and abundance of intestinal flora in patients with advanced S. japonicum infection were lower than those in patients with chronic S. japonicum infection. Furthermore, Prevotella 9, Subdoligranulum, Ruminococcus torques, Megamonas and Fusicatenibacter seemed to have potential to discriminate different stages of S. japonicum infection and to act as biomarkers for diagnosis. Function prediction analysis revealed that microbiota function in the chronic group was focused on translation and cell growth and death, while that in the advanced group was concentrated on elevating metabolism-related functions.
CONCLUSIONS
Our study demonstrated that alteration in gut microbiota in different stages of S. japonicum infection plays a potential role in the pathogenesis of transition from chronic to advanced S. japonicum infection. However, further validation in the clinic is needed, and the underlying mechanism requires further study.
Topics: Humans; Animals; Schistosomiasis japonica; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Feces; Intestines; Schistosoma japonicum
PubMed: 36345042
DOI: 10.1186/s13071-022-05539-6