Differential expression of chemokine and matrix re-modelling genes is associated with contrasting schistosome-induced hepatopathology in murine models

Autor: Donald P. McManus, Grant A. Ramm, Carly R. Perry, Deborah J. Stenzel, Geoffrey N. Gobert, Melissa L. Burke
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Chemokine
Neutrophils
Gene Expression
Pathogenesis
Schistosoma japonicum
Rodent Diseases
Mice
Gene expression
Molecular Cell Biology
Schistosomiasis
Immune Response
TIMP1
Regulation of gene expression
Mice
Inbred BALB C
biology
Histocytochemistry
lcsh:Public aspects of medicine
060500 MICROBIOLOGY
Genomics
Immunohistochemistry
Host-Pathogen Interaction
Infectious Diseases
Liver
Schistosomiasis japonica
Medicine
Female
Chemokines
Metabolic Networks and Pathways
Research Article
Neglected Tropical Diseases
lcsh:Arctic medicine. Tropical medicine
lcsh:RC955-962
Immunology
Immunopathology
Microbiology
Matrix Metalloproteinases
Secreted
medicine
Parasitic Diseases
Animals
Biology
Microarray analysis techniques
Gene Expression Profiling
Public Health
Environmental and Occupational Health
lcsh:RA1-1270
medicine.disease
Microarray Analysis
Molecular biology
Gene expression profiling
Eosinophils
Disease Models
Animal
Gene Expression Regulation
biology.protein
Mice
Inbred CBA
Parasitology
CCL24
Genome Expression Analysis
Zdroj: PLoS Neglected Tropical Diseases, Vol 5, Iss 6, p e1178 (2011)
PLoS Neglected Tropical Diseases
ISSN: 1935-2735
1935-2727
Popis: 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.
Author Summary Schistosomiasis is a significant cause of morbidity and mortality in the tropical world although its true burden has been historically underestimated. Millions of people currently endure severe pathology as a result of schistosome infections, although some individuals appear to be less susceptible to infection despite constant parasite exposure. A similar range of disease susceptibility is evident in different strains of inbred mice infected with schistosomes, thereby mirroring the clinical situation. 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. Certain genes expressed in particular cohorts of mice and humans may be associated with the development of severe pathology, or may confer a protective phenotype. This murine study highlights some key molecular aspects of chronic schistosomiasis which may be responsible for the development of both mild and severe pathology, and provides a bench mark for studying the mechanisms of schistosome-induced disease in humans.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje