Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis?

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  Figure 4. Proposed roles of individual Toll-like receptors in viral myocarditis. Based on the current evidence, the different TLRs take on different roles in the viral myocarditis disease process. The intracellular TLRs and TLR4 and TLR10 recognise virus-related PAMPs. The majority of TLRs are able to interact with DAMPs. MyD88 and TRIF are key molecules in the TLR signalling pathways. MyD88 influences CAR expression, which functions as a viral receptor. Deficiency or stimulation of individual TLRs or associated molecules differently impacts outcomes in the setting of viral myocarditis (myocardial viral load, myocardial lesions, cardiac contractility and mortality). * denotes generalisation based on the majority of findings reported in literature. Abbreviations: CAR, coxsackievirus-adenovirus receptor; DAMP, damage-associated molecular pattern; MyD88, myeloid differentiation primary response gene 88; PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; TRIF, TIR-domain-containing adaptor protein-inducing interferon-β.

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  Figure 1. Simplified overview of the MyD88-dependent and -independent signalling pathways in Toll-like receptor activation. TLRs localise to the cell surface or intracellular compartments (such as endosomes, (endo)lysosomes and endoplasmic reticulum). Differential adaptor molecules initiate specific signalling pathways in different TLR family members. A detailed description of the pathways can be found in the text. Full lines indicate direct interaction. Dashed lines indicate indirect linkage. Abbreviations: AP-1, activator protein-1; IC, intracellular; DAMP, damage-associated molecular pattern; IFN, interferon; IRF, interferon regulatory transcription factor; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor kappa B; PAMP, pathogen-associated molecular pattern; TAK, TGF-β-activating kinase; TLR, Toll-like receptor; TRAF, TNFR-associated factor; TRIF, TIR-domain-containing adaptor protein-inducing interferon-β.

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  Figure 2. The different phases of viral myocarditis. The susceptibility phase refers to the predisposing factors which make that only a minority of virally infected individuals develops myocarditis. In phase I, the virus infects and replicates in the heart, causing tissue damage without involvement of the host immunity. The insulting pathogen and the tissue damage inflicted in phase I initiate a host immune response in phase II. At first, the innate immunity battles the intruding microbe, followed by an adaptive immune response. For the majority of patients, repair in phase III leads to complete recovery. However, in some, the tissue damage will result in localised scar tissue. A small fraction of patients develops cardiac dysfunction, with mostly a dilated phenotype in this context. Abbreviations: Ab, antibody; DAMPs, damage-associated molecular patterns; DC, dendritic cell; MF, myocardial fibrosis; NK, natural killer; PAMPs, pathogen-associated molecular patterns.

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  Figure 3. Proposed roles of Toll-like receptors in viral myocarditis. Every phase of the myocarditis disease process has several associations with Toll-like receptors (TLRs), although for some the evidence is limited. These include aspects where TLRs are considered beneficial (green plane) as well as elements where TLRs potentially confer harm to the host (red plane). The ratio between both aspects determines the overall impact of TLRs on the disease process, as indicated by the weighing balance. Phase 0: TLR sex differences have been put forward as explanation for the sex bias in viral myocarditis (in which the female sex offers protection). The impact of sex hormones could run through TLR modulation. Genetic differences in TLRs are among the factors that influence host susceptibility to viral myocarditis. Phase 1: TLRs can induce autophagy and viruses can use autophagosomes as a platform for their replication. MyD88 impacts expression of CAR, an important viral receptor. MAPK family members seem to have a role in CVB replication and apoptosis regulation. Activation of MAPK pathways leads to intracellular calcium mobilisation during viral replication, contributing to cell death. Phase 2:…