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Published on: September 13, 2018
Coxsackieviral replication and pathogenicity: lessons from gene modified animal models
1Deutsches Herzzentrum and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Lazarettstrasse 36, 80636 Munich, Germany rwessely@dhm.mhn.de
Abstract:
Coxsackieviruses have been implicated in the pathogenesis of human myocarditis and some forms of dilated cardiomyopathy. A considerable portion of our knowledge about the pathophysiology of viral heart disease is derived from animal studies. In particular, investigations utilising gene-targeted mice provide valuable new insights into various aspects of viral pathogenicity and host factors involved in the control of viral replication. This review focuses on models in cell culture and transgenic animals mimicking coxsackieviral persistence, demonstrating that remarkably low persisting levels of replication-restricted coxsackieviral genomes are associated with an induction of a cytopathic effect in cardiac myocytes, leading to dilated cardiomyopathy in a transgenic mouse model. In this particular animal model, a phenotype is revealed which closely resembles the major hallmarks of human dilated cardiomyopathy. The impact of the innate immune system on coxsackieviral replication is demonstrated by studies in gene-targeted mice deficient of either type I or type II interferon signalling, which have indicated that type I but not type II interferons are essential for the control of early viral replication and survival of coxsackieviral infection.
Insights
Low levels of persistent coxsackieviral genomes can cause dilated cardiomyopathy in mice. Type I interferons are crucial for controlling viral replication and survival during coxsackieviral infections.
Area of Science:
- Virology
- Cardiology
- Immunology
Background:
- Coxsackieviruses are linked to human myocarditis and dilated cardiomyopathy.
- Animal models, especially gene-targeted mice, are vital for understanding viral heart disease.
- Viral persistence and host immune responses are key factors in pathogenesis.
Purpose of the Study:
- To review cell culture and transgenic animal models of coxsackieviral persistence.
- To investigate the link between persistent viral genomes and cardiac pathology.
- To elucidate the role of innate immunity, specifically interferon signaling, in coxsackieviral infection.
Main Methods:
- Utilized cell culture models to study coxsackieviral persistence.
- Employed transgenic mice to mimic viral persistence and cardiac effects.
- Examined gene-targeted mice deficient in type I or type II interferon signaling.
Main Results:
- Low levels of persistent, replication-restricted coxsackieviral genomes induced a cytopathic effect in cardiac myocytes.
- A transgenic mouse model exhibited a phenotype closely resembling human dilated cardiomyopathy.
- Type I interferons, but not type II, were essential for controlling early viral replication and survival.
Conclusions:
- Persistent coxsackieviral genomes, even at low levels, can lead to dilated cardiomyopathy.
- Transgenic mouse models effectively replicate key features of human dilated cardiomyopathy.
- Type I interferon signaling is critical for host defense against coxsackieviral infections.
