Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice
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Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice. / Stein, Elisabeth A; Pinkert, Sandra; Becher, Peter Moritz; Geisler, Anja; Zeichhardt, Heinz; Klopfleisch, Robert; Poller, Wolfgang; Tschöpe, Carsten; Lassner, Dirk; Fechner, Henry; Kurreck, Jens.
In: J INFECT DIS, Vol. 211, No. 4, 15.02.2015, p. 613-622.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice
AU - Stein, Elisabeth A
AU - Pinkert, Sandra
AU - Becher, Peter Moritz
AU - Geisler, Anja
AU - Zeichhardt, Heinz
AU - Klopfleisch, Robert
AU - Poller, Wolfgang
AU - Tschöpe, Carsten
AU - Lassner, Dirk
AU - Fechner, Henry
AU - Kurreck, Jens
N1 - © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - BACKGROUND: Coxsackievirus B3 (CVB3) is a major heart pathogen against which no therapy exists to date. The potential of a combination treatment consisting of a proteinaceous virus receptor trap and an RNA interference-based component to prevent CVB3-induced myocarditis was investigated.METHODS AND RESULTS: A soluble variant of the extracellular domain of the coxsackievirus-adenovirus receptor (sCAR-Fc) was expressed from an adenoviral vector and 2 short hairpin RNAs (shRdRp2.4) directed against CVB3 were delivered by an adeno-associated virus (AAV) vector. Cell culture experiments revealed additive antiviral activity of the combined application. In a CVB3-induced mouse myocarditis model, both components applied individually significantly reduced inflammation and viral load in the heart. The combination exerted an additive antiviral effect and reduced heart pathology. Hemodynamic measurement revealed that infection with CVB3 resulted in impaired heart function, as illustrated by a drastically reduced cardiac output and impaired contractility and relaxation. Treatment with either sCAR-Fc or shRdRp2.4 significantly improved these parameters. Importantly, the combination of both components led to a further significant improvement of heart function.CONCLUSIONS: Combination of sCAR-Fc and shRdRp2.4 exerted additive effects and was significantly more effective than either of the single treatments in inhibiting CVB3-induced myocarditis and preventing cardiac dysfunction.
AB - BACKGROUND: Coxsackievirus B3 (CVB3) is a major heart pathogen against which no therapy exists to date. The potential of a combination treatment consisting of a proteinaceous virus receptor trap and an RNA interference-based component to prevent CVB3-induced myocarditis was investigated.METHODS AND RESULTS: A soluble variant of the extracellular domain of the coxsackievirus-adenovirus receptor (sCAR-Fc) was expressed from an adenoviral vector and 2 short hairpin RNAs (shRdRp2.4) directed against CVB3 were delivered by an adeno-associated virus (AAV) vector. Cell culture experiments revealed additive antiviral activity of the combined application. In a CVB3-induced mouse myocarditis model, both components applied individually significantly reduced inflammation and viral load in the heart. The combination exerted an additive antiviral effect and reduced heart pathology. Hemodynamic measurement revealed that infection with CVB3 resulted in impaired heart function, as illustrated by a drastically reduced cardiac output and impaired contractility and relaxation. Treatment with either sCAR-Fc or shRdRp2.4 significantly improved these parameters. Importantly, the combination of both components led to a further significant improvement of heart function.CONCLUSIONS: Combination of sCAR-Fc and shRdRp2.4 exerted additive effects and was significantly more effective than either of the single treatments in inhibiting CVB3-induced myocarditis and preventing cardiac dysfunction.
KW - Animals
KW - Antiviral Agents/metabolism
KW - Coxsackievirus Infections/drug therapy
KW - Disease Models, Animal
KW - Dose-Response Relationship, Drug
KW - Enterovirus B, Human/drug effects
KW - Genetic Therapy/methods
KW - HeLa Cells
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Myocarditis/drug therapy
KW - RNA Interference
KW - RNA, Small Interfering/genetics
KW - Receptors, Virus/genetics
KW - Viral Load/drug effects
U2 - 10.1093/infdis/jiu504
DO - 10.1093/infdis/jiu504
M3 - SCORING: Journal article
C2 - 25193982
VL - 211
SP - 613
EP - 622
JO - J INFECT DIS
JF - J INFECT DIS
SN - 0022-1899
IS - 4
ER -