**1. Introduction**

Myocarditis is a potentially life-threatening heart disease affecting both children and adults which presents with a broad spectrum of clinical manifestations. Symptoms range from asymptomatic infection to a fulminant course that rapidly progresses to dilated cardiomyopathy (DCM) and heart failure. Viral infection of the heart is a major cause of acute myocarditis, leading to myocardial inflammation and tissue damage. Cellular infiltration in acute viral myocarditis may be caused by direct cytopathic effects of the virus, pathologic responses to persistent viral replication as well as autoimmunity triggered by the virus (Liu and Mason, 2001; Bowles and Vallejo, 2003; Linde et al., 2007; Rose et al., 2009; Rutschow et al., 2010). The cardiovirulence of the viral agent, together with the host´s genetic susceptibility and the variability in the innate and acquired immune system, appear to determine the extent of the inflammatory reaction, thereby predicting clinical outcome (Kindermann et al., 2008).

Recently, meaningful advances have been made in our understanding of cellular mechanisms that are aimed to suppress viral propagation in inflammatory heart disease. In the first line of defense against viral replication, the host´s innate immune system is activated by unspecific, albeit effective interactions of cellular receptors with distinct pathogen-derived ligands. A variety of pattern-recognition receptors have been shown to be implicated in the detection of invading microbial agents (Kawai and Akira, 2010; Takeuchi and Akira, 2010). Upon viral infection of the heart, different signal pathways initiate an inflammatory response and orchestrate the concerted anti-viral defense machinery in a complex manner. Toll-like and RIG-I-like receptors are essential for the recognition of pathogen-associated molecular patterns and their activation induces intracellular signalling pathways which lead to the production of pro-inflammatory cytokines, chemokines, and interferons (Bowles and Vallejo, 2003; Fairweather et al., 2005; Triantafilou et al., 2005; Frantz et al., 2007; Linde et al., 2007; Yajima and Knowlton, 2009; Kawai and Akira, 2010; Takeuchi and Akira, 2010; Yamamoto and Takeda, 2010; Zhu and Mohan, 2010). Vice verse, interferons appear to induce the expression of a subset of toll-like receptors (Khoo et al., 2011). Type I interferons execute anti-viral responses by modulating cell growth,

Pattern-Recognition Receptors

2006; Rose, 2009).

(Bock et al., 2010).

**3. Toll-like receptors in the inflamed heart** 

Sensing Viral Infection in Myocarditis and Inflammatory Heart Disease 203

myocarditis is comparably low, even when applying modern molecular biological techniques, probably because, due to sampling error, the diagnostic accuracy of endomyocardial biopsy remains a significant limitation (Magnani and Dec, 2006; Ellis and Di Salvo, 2007). The Dallas criteria, originally proposed in an effort to standardize the histopathologic diagnosis of myocarditis, have been shown to be of limited use for epidemiological investigations (Magnani and Dec, 2006; Ellis and Di Salvo, 2007). Thus, despite recent advances in the recognition of myocardial inflammation, the true incidence

The spectrum of clinical manifestations of viral myocarditis is extensive, ranging from asymptomatic infection to fever, myalgias, palpitations, exertional dyspnea, and hemodynamic collapse. Fulminant myocarditis may lead to systolic failure, malignant ventricular arrhythmias and sudden cardiac death (Baughman, 2005; Magnani and Dec, 2006; Rose, 2009, Blauwet and Cooper, 2010). The cardiac symptoms may also be present in more chronic forms of DCM, therefore contributing much to the difficulties in establishing the correct diagnosis. The main reason for the clinical variability appears to lie in the characteristics of the viral agent, together with the host´s innate immune system and genetic susceptibility to infection. Given the diversity and insidious onset of clinical manifestations, endomyocardial biopsy in combination with other techniques such as immunohistochemistry, serological analyses, PCR and *in situ* hydridization remains the gold standard for the detection of virus-induced myocardial inflammation (Magnani and Dec,

Although, in severely affected individuals, fulminant viral myocarditis can lead to rapid progressive heart failure, the disease usually resolves spontaneously without persisting ventricular dysfunction (Baughman, 2005; Magnani and Dec, 2006; Rose, 2009, Blauwet and Cooper, 2010). Continuing cardiovascular symptoms in the absence of ventricular compromise may indicate that chronic persistent myocarditis has developed, which is characterized by the maintenance of lymphocytic infiltrates combined with foci of myocyte necrosis. Whereas it has been well-established that chronic active myocarditis can induce heart failure, there is still a controversy with respect to the causal relationship of asymptomatic viral infections for the pathogenesis of idiopathic DCM (Yajima and Knowlton, 2009). Several studies have suggested an association between viral persistence in the myocardium and the development of DCM. However, the etiologic significance of viral genomes detected in endomyocardial biopsies from DCM patients is currently unknown

Despite a wealth of information regarding the symptomatology and clinical course of the disease, the complex pathophysiological mechanisms underlying inflammatory heart disease are only partially understood. Lessons learned from transgenic mouse models have shed some light on the essential role of endogenous receptors and transcriptional regulators engaged in early anti-viral response. From clinical and animal studies we know that the host´s innate immune system acts as the first line of defense against viral replication in a wide array of pathogenic viruses. The innate immune system, which senses pathogen invasion and primes antigen-specific adaptive immunity, has long been considered to be only non-specific and somewhat simpler than that of the adaptive system. However, recent findings on pattern-recognition receptors and their downstream signalling pathways have

and prevalence of acute viral myocarditis is still unknown.

establishing an anti-viral state and influencing the activation of various immune cells. These potent anti-viral cytokines are best known for their role as innate immune mediators (Yajima and Knowlton, 2009). In the course of viral myocarditis, apoptotic signalling pathways are activated and modulate disease pathogenesis. However, cardiotropic viruses have evolved a battery of highly specific strategies to circumvent this innate protective response of the host and successfully replicate in cardiomyocytes (Versteeg and García-Sastre, 2010). Viral factors with or without homology to host proteins specifically target key components of the anti-viral defense machinery, some of which are transcription factors involved in establishing an anti-viral state.

In the present review we focus on the contribution of pattern-recognition receptors engaged in the early response cascade against cardiotropic viruses. In particular, we report on different signal transduction pathways emerging from membrane-associated and cytosolic receptors that inhibit viral dissemination and, furthermore, give a brief overview of the various adaptor molecules involved in these pathways. Not covered in this review are the diverse viral mechanisms for antagonizing the innate immune response and the precise cellular actions of cytokines in executing this anti-viral defense. Understanding the exact mechanisms by which viral components activate pattern-recognition receptors in the heart and modify gene expression profiles may help to improve novel therapeutic regimes for the treatment of viral myocarditis (Topkara et al., 2010).
