Unknown,Transcriptomics,Genomics,Proteomics

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Characterising Host Gene Expression during the Recovery from Hepatic Schistosomiasis Japonica

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Geoffrey Gobert

PROVIDER: E-GEOD-59276 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Project description:The objective of this study was to investigate which genes are important for Streptococcus pyogenes during intracellular survival in human macrophages. Streptococcus pyogenes is an important human pathogen, which has recently gained recognition as an intracellular microorganism during the course of severe invasive infections such as necrotizing fasciitis. Although the surface anchored M protein has been identified as a pivotal factor affecting phagosomal maturation and S. pyogenes survival within macrophages, the overall transcriptional profile required for the pathogen to adapt and persist intracellularly is yet unknown. To address this, gene expression profiles of S. pyogenes within human macrophages were determined and compared to those of extracellular bacteria using customized microarrays and real-time qRT-PCR. In order to model the early phase of infection involving adaptation to the intracellular compartment, samples were collected 2h post-infection and within 2 h post infection, the expression of 145 streptococcal genes was significantly altered in the intracellular environment. The majority of differentially regulated genes were associated with metabolic and energy-dependent processes. Key upregulated genes in early phase intracellular bacteria were ihk and irr, encoding a two-component gene regulatory system (TCS). We observed that an isogenic S. pyogenes mutant deficient in ihk/irr displayed significantly reduced bacterial counts as compared to wild-type bacteria following infection of macrophages. Comparison of gene expression of selected genes at 2h and 6h post-infection revealed a dramatic shift in response regulators over time with a down-regulation of ihk/irr genes concurrent with an upreguation of the well-studied covR/S two component regulator. In reinfection assays, intracellular bacteria from the 6h time point exhibited significantly greater survival within macrophages than did bacteria collected at the 2h time point. The findings illustrate how gene expression of S. pyogenes during the intracellular life cycle is fine-tuned by temporal expression of specific two-component systems. Five samples with three biological replicates are analysed. Each open reading frame in triplicate (three technical replicas per sample). Resulting in 6-9 data points per gene per condition. The extracellular bacteria are control samples and the internal control is the house-keeping gene gyrase.

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Characterising Host Gene Expression during the Recovery from Hepatic Schistosomiasis Japonica

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