Prevention of Cardiac Dysfunction in Acute Coxsackievirus B3 Cardiomyopathy by Inducible Expression of a Soluble Coxsackievirus-Adenovirus Receptor

Pinkert, Sandra; Westermann, Dirk; Wang, Xiaomin; Klingel, Karin; Dörner, Andrea; Savvatis, Konstantinos; Größl, Tobias; Krohn, Stefanie; Tschöpe, Carsten; Zeichhardt, Heinz; Kotsch, Katja; Weitmann, Kerstin; Hoffmann, Wolfgang; Schultheiss, Heinz‐Peter; Spiller, O. Brad; Poller, Wolfgang; Fechner, Henry

doi:10.1161/circulationaha.108.845339

Cited by 69 publications

(46 citation statements)

References 37 publications

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“…They may also impact the application of the virus receptor trap sCAR-Fc as an antiviral treatment. The antiviral action of sCAR-Fc against CVB infection in vitro and in vivo has been extensively examined by us and by other groups (32,(42)(43)(44). Largescale production of sCAR-Fc in animal cells is inefficient and costly, and the production of glycosylated sCAR-Fc is a limiting factor for clinical applications.…”

Section: Discussionmentioning

confidence: 99%

The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection

Pinkert

Röger

Kurreck

et al. 2016

J Virol

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The coxsackievirus and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily (IgSF) and functions as a receptor for coxsackie B viruses (CVBs). The extracellular portion of CAR comprises two glycosylated immunoglobulin-like domains, D1 and D2. CAR-D1 binds to the virus and is essential for virus infection; however, it is not known whether D2 is also important for infection, and the role of glycosylation has not been explored. To understand the function of these structural components in CAR-mediated CVB3 infection, we generated a panel of human (h) CAR deletion and substitution mutants and analyzed their functionality as CVB receptors, examining both virus binding and replication. Lack of glycosylation of the CAR-D1 or -D2 domains did not adversely affect CVB3 binding or infection, indicating that the glycosylation of CAR is not required for its receptor functions. Deletion of the D2 domain reduced CVB3 binding, with a proportionate reduction in the efficiency of virus infection. Replacement of D2 with the homologous D2 domain from chicken CAR, or with the heterologous type C2 immunoglobulin-like domain from IgSF11, another IgSF member, fully restored receptor function; however, replacement of CAR-D2 with domains from CD155 or CD80 restored function only in part. These data indicate that glycosylation of the extracellular domain of hCAR plays no role in CVB3 receptor function and that CAR-D2 is not specifically required. The D2 domain may function largely as a spacer permitting virus access to D1; however, the data may also suggest that D2 affects virus binding by influencing the conformation of D1. IMPORTANCE An important step in virus infection C oxsackie B viruses (CVBs) initiate infection of their host cells by interaction with the coxsackievirus and adenovirus receptor (CAR). An additional cell surface protein, decay-accelerating factor (DAF), promotes binding to the cell surface but is not sufficient for infection (1-3). CAR is a member of the immunoglobulin superfamily (IgSF) and is composed of two extracellular immunoglobulin-like domains, D1 (amino acid [aa] 20 to 139) and D2 (aa 142 to 229), as well as a typical hydrophobic transmembrane domain (TMD; aa 236 to 258) and an internal cytoplasmic domain (ICD; aa 259 to 365) (4). The extracellular immunoglobulin-like domains vary in their secondary structure by different ␤-strand folding. Whereas D1 shows a typical V-type fold structure, D2 has a C2-type immunoglobulin fold (5, 6). Several studies indicate a primary role for the D1 domain in CAR interactions with CVB3 (7) and adenovirus (8), as well as in CAR/CAR homophilic interactions (9-11). Although the isolated D1 domain, produced in Escherichia coli, binds adenovirus efficiently (8), the same D1 domain was found to bind poorly to CVB3 (7), suggesting a possible supporting role for the D2 domain during CAR/ CVB3 interaction.Numerous picornavirus receptors are members of the IgSF: intercellular adhesion molecule-1 (ICAM-1) is a receptor for coxsackievirus A21 (CAV21) and the ma...

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Section: Discussionmentioning

confidence: 99%

The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection

Pinkert

Röger

Kurreck

et al. 2016

J Virol

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“…HeLa cells were transduced with an adenoviral vector (AdG12) expressing the fusion protein of the extracellular domain of CAR and the carboxyl terminus of the human IgG1 Fc domain (sCAR-Fc) in the presence of doxycycline (Dox) (52). After transduction, cells were cultured for 3 days and Dox was added daily at a concentration of 1 g/ml (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Virus-Host Coevolution in a Persistently Coxsackievirus B3-Infected Cardiomyocyte Cell Line

Pinkert

Klingel²,

Lindig

et al. 2011

J Virol

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“…These recombinant CAR-fragment crystallization and decay-accelerating factor-fragment crystallization proteins competitively bind to soluble viral particles and aid in viral-specific activation of the innate and adaptive immunity. [200][201][202][203] Simultaneous administration of soluble CAR-fragment crystallization and small interfering RNA targeting CVB3 genome exerts synergistic antiviral activity in the treatment of a persistently infected cardiac cell line in vitro. 204 However, the utility of recombinant proteins in disease treatment needs more optimization to avoid unexpected side effects.…”

Section: Pathogen Inhibitionmentioning

confidence: 99%

Myocarditis

Gabriel

Luo

Qiu

et al. 2016

Circulation Research

411

354

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Prevention of Cardiac Dysfunction in Acute Coxsackievirus B3 Cardiomyopathy by Inducible Expression of a Soluble Coxsackievirus-Adenovirus Receptor

Abstract: Background-Group

Cited by 69 publications

References 37 publications

The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection

The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection

Virus-Host Coevolution in a Persistently Coxsackievirus B3-Infected Cardiomyocyte Cell Line

Myocarditis

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