Coxsackievirus B3 modulates cardiac ion channels

Abstract

Infections with coxsackieviruses of type B (CVBs), which are known to induce severe forms of acute and chronic myocarditis, are often accompanied by ventricular arrhythmias and sudden cardiac death. The mechanisms underlying the development of virus-induced, life-threatening arrhythmias, which are phenotypically similar to those observed in patients having functionally impaired cardiac ion channels, remain, however, enigmatic. In the present study, we show, for the first time, modulating time-dependent effects of CVB3 on the cardiac ion channels KCNQ1, hERG1, and Cav1.2 in heterologous expression. Channel protein abundance in cellular plasma membrane and patterns of their subcellular distribution were altered in infected murine hearts. The antiviral compound AG7088 did not prevent these effects on channels. In silico analyses of infected human myocytes suggest pronounced alterations of electrical and calcium signaling and increased risk of arrhythmogenesis. These modifications are attenuated by the common Asian polymorphism KCNQ1 P448R, a genetic determinant preventing coxsackievirus-induced effects in vitro. This study provides a previously unknown explanation for the development of arrhythmias in enteroviral myocarditis, which will help to develop therapeutic strategies for arrhythmia treatment.

Viral dependence on cellular ion channels – an emerging anti-viral target?

“…Other cardiac ion channel-virus interactions of note include coxsackievirus B3 (CVB3), which alters the cellular distribution of L-type Ca 2+ channels, hERG1 channels and K v LQT1 (K v 7.1) channels during infection [40]. In mice, CVB3 was also shown to replicate to higher titres in the hearts of mutant animals deficient in the K ir 6.1 subunit of K ATP channels, suggesting that K ATP channel deregulation has a critical impact on innate anti-viral immunity in the heart.…”

“…In mice, CVB3 was also shown to replicate to higher titres in the hearts of mutant animals deficient in the K ir 6.1 subunit of K ATP channels, suggesting that K ATP channel deregulation has a critical impact on innate anti-viral immunity in the heart. CVB3-mediated ion channel alterations appear to be a requirement for virus persistence and may contribute to the arrhythmia frequently observed in CVB3 patients [40,41].…”

Electrophysiological alterations in a murine model of chronic coxsackievirus B3 myocarditis

“…Coxsackievirus B3 (CVB3) is a non-enveloped virus with a single-stranded and positive polarity RNA genome and belongs to the picornavirus family of the enterovirus genus [1, 2]. Six serotypes of coxsackievirus of group B have been identified (CVB1-6) which cause diverse diseases as pancreatitis [3–5], meningitis or encephalitis [6] and myocarditis [1, 2, 5, 7–11].…”

“…Six serotypes of coxsackievirus of group B have been identified (CVB1-6) which cause diverse diseases as pancreatitis [3–5], meningitis or encephalitis [6] and myocarditis [1, 2, 5, 7–11]. Enteroviral infections due to CVB1-5 are present in around 5 million U.S. citizens and approximately 600,000 suffer from myocardial infection and myocarditis, mainly due to CVB serotypes 1,3 and 5 [1].…”

Structural interplay of KV7.1 and KCNE1 is essential for normal repolarization and is compromised in short QT syndrome 2 (KV7.1-A287T)

“…Impaired I Ks function can result from gene mutations, from pharmacological intervention, 8 and/or from myocardial infections with Coxsackie virus B3, as shown in a mouse model 9 . Unbalanced ion fluxes during cardiac action potentials can thus lead to cardiac arrhythmias and potentially cause sudden cardiac death 10, 11, 12, 13, 14, 15…”