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Salmonella typhimurium Infection Reduces Schistosoma japonicum Worm Burden in Mice.

ABSTRACT: Coinfection of microorganisms is a common phenomenon in humans and animals. In order to further our understanding of the progress of coinfection and the possible interaction between different pathogens, we have built a coinfection mouse model with Schistosoma japonicum and Salmonella typhimurium, and used this model to investigate the systemic metabolic and immune responses using NMR-based metabonomics and immunological techniques. Our results show that Salmonella typhimurium (ATCC14028) infection reduces the number of adult schistosomal worms and eggs, relieves symptoms of schistosomiasis and also abates the mortality of mice infected by Schistosoma japonicum. In addition, Salmonella typhimurium infection counteracts the metabolic disturbances associated with schistosomiasis, which was reflected by the reverted levels of metabolites in coinfected mice, compared with the Schistosoma japonicum infected mice. Furthermore, immune analyses also indicate that shift of the immune response to different pathogens is a result of indirect interactions between Schistosoma japonicum and Salmonella typhimurium within the host. Salmonella typhimurium infection can ameliorate Schistosoma japonicum-caused schistosomiasis in BALB/c mice, which is most likely due to inverse immune polarization. Our work provides an insight into coinfection between Schistosoma japonicum and Salmonella typhimurium, and may further contribute to the development of new tools for controlling Schistosoma japonicum-associated diseases.

SUBMITTER: Zhu X

PROVIDER: S-EPMC5430953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dioecious flatworms of the genus Schistosoma causes schistosomiasis, which is a major public health problem in developing countries. Acquiring detailed knowledge of schistosome-host interactions may aid in the development of novel strategies for schistosomiasis control. MicroRNAs (miRNAs) are involved in processes such as development, cell proliferation, metabolism, and signal transduction. Circulating miRNAs not only serve as a novel class of biomarkers of many diseases but also regulate target gene expression in recipient cells, which are similar to hormones.In the present study, we used miRNA microarrays to determine the profile of circulating miRNAs associated with S. japonicum infection of mice. The biological functions of the altered levels of miRNAs and their target genes were predicted using bioinformatics. Expression levels of selected miRNAs and their target genes were further analyzed by quantitative RT-PCR.Our study identified 294 and 189 miRNAs in infected mice that were expressed in two independent experiments at levels???2-fold higher or???0.5-fold lower, respectively, compared with uninfected mice. Thirty-six of the same miRNAs were detected in these analyses. Moreover, pathway analyses indicated that most of these miRNAs are putatively involved in signaling pathways associated with pathogenesis, such as Wnt and MAPK signaling. Further, we show an inverse correlation between the circulating levels of these miRNAs and their target genes, suggesting that changes in miRNA expression may cause aberrant expression of genes such as Creb1 and Caspase-3 in mice infected with S. japonicum.Our study shows significant differences in the levels of circulating miRNAs between S. japonicum infected mice and uninfected mice. In particular, the altered levels of miR-706 and miR-134-5p were associated with altered levels of expression of the Caspase-3 and Creb1 genes, respectively, suggesting that circulating miRNAs may serve as important mediators of the pathology of hepatic schistosomiasis. Additionally, our results are expected to provide new insights for further understanding the mechanisms of schistosome-host interaction that may facilitate in the development of novel interventions for alleviating the symptom of S. japonicum infection as well as for preventing and treating schistosomiasis.

Project description:BackgroundSchistosomiasis is a parasitic disease infecting more than 200 million people in the world. Although chemotherapy targeting on killing schistosomes is one of the main strategies in the disease control, there are few effective ways of dealing with liver fibrosis caused by the parasite infection in the chronic and advanced stages of schistosomiasis. For this reason, new strategies and prospective drugs, which exert antifibrotic effects, are urgently required.Methods and findingsThe antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica. Murine fibrosis models were established by cutaneous infection with 14 ± 2 Schistosoma japonicum cercariae. Then, the mice of both chronic (8 weeks post-infection) and advanced (15 weeks post-infection) schistosomiasis were treated by gavage of praziquantel (250 mg/kg, once daily for 3 days) to eliminate worms, and followed by praziquantel anti-fibrosis treatment (300 mg/kg, twice daily for 30 days). The fibrosis-related parameters assessed were areas of collagen deposition, content of hydroxyproline and mRNA expressions of Col1?1, Col3?1, ?-SMA, TGF-?, MMP9, TIMP1, IL-4, IL-10, IL-13 and IFN-? of liver. Spleen weight index, alanine aminotransferase activity and liver portal venous pressure were also measured. The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension. In order to confirm the anti-fibrotic properties of praziquantel, we established a CCL(4)-induced model and revealed that CCL(4)-induced liver fibrosis was inhibited by PZQ treatment for 30 days. Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs). It is indicated that mRNA expressions of Col1?1, Col3?1, ?-SMA, TGF-?, MMP9 and TIMP1 of HSCs were all inhibited after praziquantel anti-parasite treatments.ConclusionsThe significant amelioration of hepatic fibrosis by praziquantel treatment validates it as a promising drug of anti-fibrosis and offers potential of a new chemotherapy for hepatic fibrosis resulting from schistosomiasis.

Project description:BackgroundThe current knowledge of immunological responses to schistosomiasis, a major tropical helminthic disease, is insufficient, and a better understanding of these responses would support vaccine development or therapies to control granuloma-associated immunopathology. CD4(+) T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis. The induction of T helper (Th)1, Th2 and T regulatory (Treg) cells and their roles in schistosome infections are well-illustrated. However, little in vivo data are available on the dynamics of Th17 cells, another important CD4(+) T cell subset, after Schistosoma japonicum infection or whether these cells and their defining IL-17 cytokine mediate host protective responses early in infection.MethodologyLevels of Th17 and the other three CD4(+) T cell subpopulations and the cytokines related to induction or repression of Th17 cell generation in different stages of S. japonicum infection were observed. Contrary to reported in vitro studies, our results showed that the Th17 cells were induced along with the Th1, Th2, Treg cells and the IFN-γ and IL-4 cytokines in S. japonicum infected mice. The results also suggested that S. japonicum egg antigens but not adult worm antigens preferentially induced Th17 cell generation. Furthermore, decreasing IL-17 with a neutralizing anti-IL-17 monoclonal antibody (mAb) increased schistosome-specific antibody levels and partial protection against S. japonicum infection in mice.ConclusionsOur study is the first to report the dynamics of Th17 cells during S. japonicum infection and indicate that Th17 cell differentiation results from the integrated impact of inducing and suppressive factors promoted by the parasite. Importantly, our findings suggest that lower IL-17 levels may result in favorable host protective responses. This study significantly contributes to the understanding of immunity to schistosomiasis and may aid in developing interventions to protect hosts from infection or restrain immunopathology.

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Salmonella typhimurium Infection Reduces Schistosoma japonicum Worm Burden in Mice.

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