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The 434(G>C) polymorphism within the coding sequence of Eosinophil Cationic Protein (ECP) correlates with the natural course of Schistosoma mansoni infection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. (Inflammation)
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2007 (English)In: International Journal of Parasitology, ISSN 0020-7519, E-ISSN 1879-0135, Vol. 37, no 12, 1359-1366 p.Article in journal (Refereed) Published
Abstract [en]

Schistosomiasis is a chronic parasitic infection with over 200 million people infected worldwide. In Schistosoma mansoni infections, parasite-derived eggs get trapped in the liver, causing the formation of granulomas, which may develop into periportal fibrosis and portal hypertension, and thus severe morbidity. Eosinophil cationic protein (ECP) is a secretory protein of eosinophil granulocytes that efficiently kills the larval stage of S. mansoni, but also affects fibroblast functions. We have investigated the prevalence of the ECP gene polymorphism 434(G>C) in two African populations, from an S. mansoni endemic area in Uganda (n = 297) and from a non-endemic area in Sudan (n - 78), and also compared these with a Swedish population (n = 209). The genotype frequencies in the Ugandan population differed significantly from both the Sudanese and Swedish populations (P < 0.001). In the Ugandan population there was a significant association between genotype and prevalence of infection (P = 0.03), with lower prevalence in subjects with the GG genotype compared with GC (P = 0.02) and CC (P = 0.03). There was also a trend towards an association with periportal fibrosis (P = 0.08) in the Ugandan population. This suggested association was confirmed when the predominant tribe (n = 212) was analysed separately (P = 0.004). Our results suggest that ECP may be an important protein, both in the immune response against S. mansoni and in the development of periportal fibrosis. The results also suggest genetic selection towards the ECP 434CC genotype in populations living in S. mansoni endemic areas.

Place, publisher, year, edition, pages
2007. Vol. 37, no 12, 1359-1366 p.
Keyword [en]
Invertebrata, Helmintha, Plathelmintha, Trematoda, Schistosoma mansoni, Parasite, Molecular biology, Fibrosis, Cytotoxicity, Infection, Protein, Eosinophil, Polymorphism
National Category
Medical and Health Sciences Biological Sciences
URN: urn:nbn:se:uu:diva-96294DOI: 10.1016/j.ijpara.2007.04.001ISI: 000249845600007PubMedID: 17507019OAI: oai:DiVA.org:uu-96294DiVA: diva2:170823
Available from: 2007-10-19 Created: 2007-10-19 Last updated: 2011-01-25Bibliographically approved
In thesis
1. Studies of Eosinophil Cationic Protein (ECP) in vivo and in vitro: Impact of Genetic and Posttranslational Modifications
Open this publication in new window or tab >>Studies of Eosinophil Cationic Protein (ECP) in vivo and in vitro: Impact of Genetic and Posttranslational Modifications
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av Eosinophil Cationic Protein (ECP) in vivo och in vitro : Effekter av genetiska och posttranslationella modifieringar
Abstract [en]

Eosinophil granulocytes are tissue dwelling leukocytes that are implicated in host defence, particularly against helminthic parasites; they also participate in most inflammatory disorders. Although eosinophils have important roles in host defence mechanisms, their actions can also be harmful to the host as in the allergic inflammation where lung epithelium is destructed due to the release of toxic granule proteins.

The focus of the present thesis work has been to characterize the molecular and functional heterogeneity of the granule protein Eosinophil Cationic Protein (ECP). We investigated a coding ECP gene polymorphism (arg97thr) in an African population endemically exposed to the Schistosoma mansoni parasite and found a correlation between ECP genotype and disease manifestations; ECP97arg was more effective in terms of host defence against the parasite, but was also correlated to development of liver fibrosis in infected subjects.

We purified ECP97arg and ECP97thr from healthy blood donors and showed that they differ in their cytotoxic activities; ECP97arg was cytotoxic whereas ECP97thr was non-cytotoxic. They did not differ in terms of RNase activity or in their ability to stimulate fibroblast-mediated collagen gel contraction.

We developed a new SELDI-TOF MS assay to enable the study of the structure of ECP in more detail and showed that ECP is produced in several glycosylated forms, and that the degree of glycosylation determines the cytotoxic activity. Enzymatic deglycosylation significantly enhanced the cytotoxic activity of highly glycosylated ECP-variants.

To summarize, in this thesis we demonstrated that the cytotoxic activity of ECP is dependent on both a gene polymorphism and post-translational modifications, and that the cytotoxic activity is distinct from other functions of ECP. We speculate that ECP is synthesised in heavily glycosylated variants as a means to protect the host from its harmful effects and that ECP is activated by deglycosylation when required at the site of inflammation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 278
Biomedicine, Eosinophil granulocyte, granular protein, ECP, gene polymorphism, cytotoxicity, SELDI-TOF MS, glycosylation, molecular and functional heterogeneity, fibrosis, Biomedicin
urn:nbn:se:uu:diva-8261 (URN)978-91-554-6989-4 (ISBN)
Public defence
2007-11-09, Enghoffsalen, Ingång 50, bv, Akademiska Sjukhuset, Uppsala, 09:15
Available from: 2007-10-19 Created: 2007-10-19Bibliographically approved

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