Antiviral and myocyte protective effects of murine interferon-β and -α₂in coxsackievirus B3-induced myocarditis and epicarditis in Balb/c mice

Abstract

The present study tested the hypothesis that murine (m)IFN-beta or mIFN-alpha(2) can eliminate cardiac viral load and protect cardiomyocytes from injury in animals infected with coxsackievirus B3 (CVB3). CVB3-inoculated male Balb/c mice exhibited signs of illness, including lethargy, progressive weight loss, and death (10% on day 3 and 100% on day 8). Cardiac viral load was high [4,277 +/- 1,009 plaque-forming units and 25 +/- 5 copies CVB3/hypoxanthine guanine phosphoribosyl transferase 1 mRNA] on day 4. The cardiac tissue exhibited severe inflammatory infiltration and myocyte damage with an average myocarditis integrated pathology score of 2.1 +/- 0.2 on day 7. Most of the mice infected with CVB3 also developed epicarditis, and 55% had intraventricular thrombi present. Treatment with mIFN-beta [2.5 to 10 million international units (MIU)/kg] dose-dependently improved the general health status in CVB3-inoculated mice, as evidenced by reduction in weight loss, prevention of death, elimination of cardiac viral load, protection of myocytes from injury, decrease in inflammatory cell infiltration, and attenuation of intraventricular thrombus formation. Treatment with 10 MIU/kg mIFN-alpha(2) resulted in a similar level of efficacy as that induced by 5 MIU/kg mIFN-beta, with the exception that mIFN-alpha(2) did not reduce cardiac CVB3 mRNA. However, mIFN-alpha(2) , but not any dose group of mIFN-beta, significantly attenuated CVB3-induced epicarditis. These data demonstrate antiviral effects for both mIFN-beta and mIFN-alpha(2), which lead to protection of the mice from CVB3-induced myocarditis. However, the potential mechanisms leading to a differential host response for the two isoforms of mIFN remain to be elucidated.

Th17 Cells Contribute to Viral Replication in Coxsackievirus B3-Induced Acute Viral Myocarditis

“…In the early stage of CVB3 infection, the direct attack on myocardial cells by the virus is the dominant pathogenic process (8). The classical theories suggest that CD4 + Th1 cells are the vital defenders against viral infection in adaptive immune responses, mostly because these cells can produce IFN-g, the essential cytokine for effective clearance of viral infections, which activate macrophages to produce NO and promote the killing of intracellular pathogens (9,10).…”

PAR-1 contributes to the innate immune response during viral infection

“…Indeed, IFN-β-deficient mice are more susceptible than WT mice to infection with CVB3 (51). Importantly, administration of IFN-α or IFN-β reduces CVB3-induced myocarditis in mice and humans (48,52,53). Similarly, the ssRNA virus influenza A activates both TLR3 and RIG-I in lung epithelial cells (54).…”

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

“…Coxsackievirus B3 (CVB3), a common enterovirus, is a major cause of myocarditis leading to iDCM in Western populations (9,10,20). Interferons (IFNs) like IFN-␤ and IFN-␥ reduce myocarditis and improve heart function in patients and animal models by reducing viral replication, suggesting that viral infections are an important cause of myocarditis cases that lead to iDCM and heart failure (18,19,39,57).…”