Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Migrating Schistosoma japonicum schistosomula induce type-2 inflammation in the murine lung

ABSTRACT: Migrating schistosomula are an important stage of the schistosome lifecycle and represent a key target for elimination of infection by natural and vaccine induced host immune responses. To gain a better understanding of how these parasites initiate a primary host immune response we have characterised the host lung response to migrating Schistosoma japonicum schistosomula using a combination of histochemistry, microarrays and quantitative cytokine analysis. Our data suggest that, during a S. japonicum infection, actively migrating schistosomula induce a Type-2 cytokine response in the lung that may support the subsequent development of a CD4+ T helper 2 (Th2) response against egg antigens. This hypothesis is supported by the fact that schistosomula and schistosome eggs are known to express important Th2-inducing antigens such as omega-1, peroxiredoxin, kappa-5 and IPSE/alpha1. The host lung response to migrating schistosomula was associated with increased numbers of macrophages and expression of markers for alternatively activated macrophages (AAMφ) in the lung. Activation of AAMφ in the lung and at the systemic level could lead to the modulation of the host immune response to favour parasite survival. Induction of these cells could also contribute to diminished inflammatory responses to, for example, allergy and asthma that are known to be associated with helminth infections. These data enhance our understanding of the mechanisms whereby schistosomes may evade the immune response and the mechanisms by which schistosome infection can help influence the host response following exposure to allergenic stimuli. The gene expression profile of the murine lung was examined at 3 days weeks post infection with 500 Schistosoma japonicum cercariae in comparison to that of uninfected controls. Microarray analysis was performed on cRNA synthesised from total RNA derived from the lungs of 3 individual mice per group.

ORGANISM(S): Mus musculus

SUBMITTER: Melissa Burke

PROVIDER: E-GEOD-27171 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In schistosomiasis japonica, the egg-induced granulomatous response and the development of extensive hepatic fibrosis is the main pathology. Information regarding the specific mechanisms associated with granuloma regression and the subsequent recovery events in the host liver are still limited. In this study, a murine model of schistosomiasis japonica was used to characterise the multicellular pathways occurring during liver regeneration. Schistosoma japonicum-infected C57BL/6 mice were administered with the drug praziquantel (PZQ), on a daily basis for five consecutive days to eliminate all adult parasites. The pathological changes of PZQ-treated groups after 3, 6 and 7 weeks post PZQ treatment were examined, along with the assessment of cellular infiltration to the liver. PZQ treatment significantly reduced the degree of splenomegaly, granuloma density and the collagen deposition of liver fibrosis. The infiltration of inflammatory cells, including neutrophils, eosinophils and macrophages to the liver were as well significantly decreased. Transcriptomic analysis revealed the significant up-regulation of fatty acid metabolism genes and the identification of peroxisome proliferator-activated receptor alpha (PPAR-α) as the upstream regulator during the process of liver recovery. Aryl hydrocarbon receptor (AhR) signalling pathway that is involved primarily in the regulation of hepatic enzymes responsible for xenobiotic metabolism was as well differentially up-regulated. These findings indicate that schistosome egg-induced fibrogenesis process is reversible, and provide a better understanding of the regression mechanisms associated with hepatic schistosomiasis. These results hold important implications for the future alleviation of this and other fibrotic diseases of clinical significance. C57BL/6 murine model infected with S. japonicum were treated orally with Praziquantel (PZQ) after 7 weeks post infection to examine the hepatic regression process following drug treatment. These PZQ-treated, non PZQ-treated and uninfected mice were then euthanised at 10, 13, and 14 weeks p.i. Livers were collected from each mice, and subjected to total RNA isolation and gene expression analysis. Microarray analysis of this study was performed using samples derived from 3 individual mice per group/time-point.

Project description:Alternatively activated macrophages (AAMφs) play important roles in a number of Th2 driven pathologies including asthma and allergy, and a number of parasitic infections. Our studies, and those of others, investigating the pathologies associated with infection with the helminth Schistosoma japonicum implicate a role for AAMφs in fibrosis and immunomodulation.. In the present study we show that S. japonicum-secreted egg antigens are able to induce the alternative activation of macrophages as characterised by the induction of Chi3l3 and Arg1 expression. Retnla, another common marker of AAMφs, was not consistently induced in these macrophages suggesting that the specific function of these cells may differ to those induced by S. mansoni and other parasites. Closer examination of the gene expression profile and functionality of these cells identified pathways independent of Retnla expression that could be important for their immunomodulatory activity such as modulating expression of T-cell co-stimulatory molecules and chemokines. In vivo generated S. japonicum soluble egg antigen stimulated AAMφs also exhibited a reduction in their phagocytic ability likely related to the induction of IL4 and decreased expression of cell surface receptors. Additionally these macrophages exhibited reduced expression of Toll-like receptors (TLRs) and an associated reduction in responsiveness to stimulation with TLR ligands. We did not observe pathways that would suggest that AAMφs have a direct profibrotic activity. Taken together, these data describe a mechanism by which alternative activation of macrophages may be induced during S. japonicum infection and highlight the importance of the context of activation in directing AAMφ phenotype and function. The gene expression profile of Schistosoma japonicum soluble egg antigen (SEA)-stimulated macrophages was compared with that of PBS stimulated controls. Macrophages were isolated from the peritoneal cavity of BALB/c mice (n=6 per group) stimulated by intraperitoneal injection with SEA or PBS. The macrophages were pooled and RNA was extracted from these cells. Microarray analysis was performed on cRNA synthesised from total RNA derived from these macrophages. The experiment was performed twice creating two biological replicates. Fold-change (relative to the respective PBS control) reported in supplementary file linked below.

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Project description:Pan-viral DNA array (PVDA) and high-throughput sequencing (HTS) are useful tools to identify novel virus of emerging diseases. However, both techniques have difficulties to identify viruses in clinical samples because of host genomic DNA (hgDNA) contamination. Both propidium monoazide (PMA) and ethidium bromide monoazide (EMA) have the capacity to bind free DNA but are cell membrane-impermeable and thus are unable to bind protected DNA and RNA such as viral genomic material. DNA modified by EMA or PMA is not amplifiable by polymerase. In order to assess the capacity of EMA or PMA to lower hgDNA, serum or lung tissue homogenates were spiked with porcine reproductive and respiratory virus (PRRSV) and were processed with different combination of treatment: with or without ultracentrifugation and incubation with or without different concentration of EMA or PMA. PVDA and HTS were used to evaluate the capacity of both techniques to detect the presence of PRRSV from each sample. Negative results were obtained by PVDA and low amount of PRRSV specific reads were obtained by HTS with untreated samples or samples treated only by ultracentrifugation. An increase capacity of PRRSV detection was observable by PVDA in EMA and PMA treated samples but PVDA best results were obtained following PMA treatment, with or without ultracentrifugation. HTS sensitivity was also improved by a treatment with EMA or PMA, but the number of reads was significantly higher in PMA treated samples. These results support the use of PMA as a treatment to increase sensitivity of PVDA and HTS. A non specific DNA probe is used as a negative hybridization control. Also, specifics probes targeting pUC19 plasmid DNA is used as a DNA array positive control as well as a localization control. Finally, there are 34 probes of 70 nucleotides spotted in duplicate were selected to target PRRSV conserved regions. A total of 80 different tests were done by DNA array in order to evaluate different treatments conditions with EMA or PMA, with or without ultracentrifugation. A total of 58 samples were tested on specific lung tissue homogenates spiked with different concentration of PRRSV and 12 samples were serum samples spiked with one concentration of PRRSV. Finally. A total of six samples

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Migrating Schistosoma japonicum schistosomula induce type-2 inflammation in the murine lung

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