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Cardiovirulent coxsackieviruses and the decay-accelerating factor (CD55) receptor
T A Martino1, M Petric, M Brown
1Center for Cardiovascular Research, Toronto Hospital, Ontario, Canada.
Insights
Group B coxsackieviruses use the decay-accelerating factor (DAF) as a cell surface receptor for infection. This interaction is crucial for virus entry and may play a role in coxsackievirus-induced heart disease pathogenesis.
Area of Science:
- Virology
- Immunology
- Cardiovascular Disease Research
Background:
- Group B coxsackieviruses (CVB) are linked to human heart diseases like myocarditis and dilated cardiomyopathy.
- The specific cell surface receptors used by cardiovirulent CVB strains for attachment and infection are largely unknown.
- Understanding these interactions is key to elucidating viral pathogenesis and developing targeted therapies.
Purpose of the Study:
- To investigate the role of decay-accelerating factor (DAF or CD55) as a cell surface receptor for cardiovirulent CVB3 strains.
- To characterize the binding interactions between CVB3 and DAF, including specific binding domains and effects on viral entry.
- To explore the potential involvement of DAF in the pathogenesis of CVB-mediated heart disease.
Main Methods:
- Utilized monoclonal antibodies (MAbs) against DAF to block CVB3 binding and infection in HeLa cells.
- Employed phosphatidylinositol phospholipase C enzyme treatment to create DAF-deficient cells and assess virus binding.
- Performed flow cytometry to monitor DAF expression changes during virus infection.
- Conducted competitive binding assays with Adenovirus type 2 (Ad2) to investigate DAF's association with other viral receptors.
Main Results:
- Anti-DAF MAbs effectively blocked CVB3 binding and infection, confirming DAF's role as an attachment receptor.
- Treatment with phosphatidylinositol phospholipase C significantly reduced virus binding, indicating dependence on DAF.
- Cardiovirulent CVB3 strains showed differential binding affinities to DAF, with binding consistently blocked by MAbs targeting SCR 2 and 3 domains.
- Virus binding and internalization led to DAF down-regulation on the cell surface.
- CVB3 did not interact with DAF-related molecules (CD35, CD46, Factor H, C4-binding protein).
- DAF was found to be associated with Ad2 receptors on HeLa cells.
Conclusions:
- Decay-accelerating factor (DAF/CD55) serves as a critical attachment receptor for cardiovirulent Group B coxsackieviruses.
- The interaction between CVB3 and DAF is important for viral entry and may contribute significantly to the pathogenesis of CVB-induced heart disease.
- DAF's role as a receptor warrants further investigation for therapeutic strategies against viral myocarditis.
Abstract:
Group B coxsackieviruses are etiologically linked with many human diseases including acute myocarditis and associated chronic dilated cardiomyopathy. Well-established CVB3 cardiovirulent strains (CVB3c(s)) with known phenotypic difference have been used to study the pathogenesis of virus-induced heart disease. The receptor-binding characteristics of cardiovirulent CVB3 are not known, but may represent one mechanism accounting for differences in disease virulence. In this study, interactions between CVB3c(s) and the decay-accelerating factor (DAF or CD55) cell surface receptor were examined. Anti-DAF monoclonal antibodies (MAbs) blocked virus binding and infection of susceptible HeLa cells. Virus binding was significantly reduced by treatment of these cells with phosphatidylinositol phospholipase C enzyme, which rendered them DAF-deficient CVB3c(s) exhibited a differential propensity for the DAF receptor, as several cardiovirulent strains interacted more strongly than others. However, virus binding and infection was always most effectively blocked by MAbs directed against the SCR 2 and 3 domains of DAF, suggesting that binding occurs at a similar site(s) on the molecule for all strains. Virus binding and internalization were associated with DAF down-regulation at the cell surface, as monitored by flow cytometry analysis. Cardiovirulent CVB3 did not interact with molecules functionally and/or structurally related to DAF, including CD35, CD46, Factor H, or C4-binding protein. Adenovirus type 2 (Ad2) does not use the DAF receptor. However, competitive binding assays between Ad2 and CVB1-6, CVB3c(s), anti-DAF MAbs, or DAF-reduced cells indicated that DAF is associated with Ad2 receptors on the HeLa cell membrane. In summary, this study indicates that DAF is an attachment receptor for cardiovirulent CVB3 and that DAF interaction may be important in the pathogenesis of CVB-mediated heart disease.