Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis

Area of Science:

• Virology
• Immunology
• Cardiology

Background:

• Group B coxsackieviral (CVB) infection is a common cause of viral myocarditis.
• p56(Lck) (Lck), a Src family kinase crucial for T cell activation, protects mice from CVB3 myocarditis.
• Extracellular signal-regulated kinase 1 and 2 (ERK-1/2) signaling can modulate cellular functions downstream of Lck.

Purpose of the Study:

• To investigate the role of ERK-1/2 in CVB3 infection within T cell lines and neonatal cardiac myocytes.
• To determine if ERK-1/2 activation by CVB3 is dependent on Lck.
• To assess the necessity of ERK-1/2 and Src kinases for CVB3 replication.

Main Methods:

• Utilized Jurkat T cells (Lck-positive) and JCaM T cells (Lck-negative) to study CVB3-induced ERK-1/2 activation.
• Employed the ERK-1/2 inhibitor UO126 and the Src inhibitor PP2 in cellular assays.
• Examined ERK-1/2 activation in cardiac myocytes and in the myocardium of infected mice (A/J and C57BL/6 strains).

Main Results:

• CVB3 rapidly activated ERK-1/2 in Jurkat T cells, but not in Lck-negative JCaM cells.
• Inhibition of ERK-1/2 reduced CVB3 titers in Jurkat cells, indicating its role in viral replication.
• CVB3-induced ERK-1/2 activation in cardiac myocytes was blocked by a Src inhibitor, and both Src and ERK-1/2 inhibition decreased viral production.
• In vivo, ERK-1/2 activation was observed in the myocardium of CVB3-infected mice, with higher activation in susceptible A/J mice compared to resistant C57BL/6 mice.

Conclusions:

• ERK-1/2 is activated by CVB3 downstream of Lck and other Src kinases in both immune and myocardial cells.
• ERK-1/2 activation is necessary for efficient CVB3 replication.
• The magnitude of ERK-1/2 activation in the heart following CVB3 infection may correlate with differential host susceptibility to viral myocarditis.