Abstract
The pathological outcomes of schistosomiasis are largely dependent on the molecular and cellular mechanisms of the host immune response. In this study, we investigated the contribution of variations in host gene expression to the contrasting hepatic pathology observed between two inbred mouse strains following Schistosoma japonicum infection. Whole genome microarray analysis was employed in conjunction with histological and immunohistochemical analysis to define and compare the hepatic gene expression profiles and cellular composition associated with the hepatopathology observed in S. japonicum-infected BALB/c and CBA mice. We show that the transcriptional profiles differ significantly between the two mouse strains with high statistical confidence. We identified specific genes correlating with the more severe pathology associated with CBA mice, as well as genes which may confer the milder degree of pathology associated with BALB/c mice. In BALB/c mice, neutrophil genes exhibited striking increases in expression, which coincided with the significantly greater accumulation of neutrophils at granulomatous regions seen in histological sections of hepatic tissue. In contrast, up-regulated expression of the eosinophil chemokine CCL24 in CBA mice paralleled the cellular influx of eosinophils to the hepatic granulomas. Additionally, there was greater down-regulation of genes involved in metabolic processes in CBA mice, reflecting the more pronounced hepatic damage in these mice. Profibrotic genes showed similar levels of expression in both mouse strains, as did genes associated with Th1 and Th2 responses. However, imbalances in expression of matrix metalloproteinases (e.g. MMP12, MMP13) and tissue inhibitors of metalloproteinases (TIMP1) may contribute to the contrasting pathology observed in the two strains. Overall, these results provide a more complete picture of the molecular and cellular mechanisms which govern the pathological outcome of hepatic schistosomiasis. This improved understanding of the immunopathogenesis in the murine model schistosomiasis provides the basis for a better appreciation of the complexities associated with chronic human schistosomiasis.
Highlights
Schistosomiasis currently afflicts over 200 million people and continues to cause debilitating disease worldwide, in developing and resource-poor countries [1] where the true global impact of the disease has been largely unacknowledged [2]
Similar variations in pathology during progressive schistosomiasis are known to occur between different mouse strains [5,6,7], such as inbred CBA, BALB/c and C57BL/6 mice, which again are likely to be attributable to differences in the modulation of host immune responses as other aforementioned contributing factors are controlled
Granuloma formation in the liver of both humans and mice is a characteristic manifestation of chronic schistosomiasis, and is largely controlled by gene signalling pathways
Summary
Schistosomiasis currently afflicts over 200 million people and continues to cause debilitating disease worldwide, in developing and resource-poor countries [1] where the true global impact of the disease has been largely unacknowledged [2]. The scope of morbidity caused by schistosomiasis japonica ranges from relatively mild hypersensitivity reactions to severe hepatic and intestinal fibrosis, granuloma formation, hepatosplenomegaly and portal hypertension [3]. This variation in human pathology appears largely dependent on the host immune response to schistosomes, and to the intensity of infection, the number of previous infections and co-infections with other parasites [4]. Schistosome-induced granuloma formation is characterised by a focussed accumulation of immune cells and collagen deposition, all of which attempt to neutralise the presence of parasitic eggs. This response is a manifestation of the host CD4+ T-cell dependent immune response against schistosome eggs lodged in the liver characterised by the production of the Th2 cytokines IL-4 and IL13 that induce granuloma formation and fibrosis [4][8]
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