P13: Protease-mediated regulation of cardiac inflammation and reverse cardiac fibrosis during viral myocarditis
Myocarditis is defined as inflammation of the myocardium and can be triggered by non-infectious and infectious agents, with viral infection representing the most common cause. In experimental models, the intraperitoneal injection (i.p.) of Coxsackie-Virus B3 (CVB3) in mice is a well-established method for inducing viral myocarditis. The progression of CVB3-induced myocarditis typically occurs in three sequential phases: (i) an initial virus-mediated myocarditis, during which direct virus cytotoxicity leads to myocardial injury, (ii) an immune-mediated phase characterized by infiltration of immune cells and inflammatory responses, (iii) a chronic phase, which may resolve with healing or virus persistence with or without ongoing inflammation. Upon infection, CVB3 replicates within cardiac cells, leading to cell lysis, which triggers recruitment of immune cells. A clear sign of acute myocarditis are mononuclear cell infiltration to control infection. While timely immune cell recruitment is essential for effective virus clearance, delayed recruitment can impair virus control and lead to impaired cardiac function.
Thesis project 1: Function of MMP13 and their cleavage products during acute viral myocarditis and reversible fibrosis.
By cleaving the ECM, MMPs can facilitate immune cell infiltration into infected tissue. However, MMPs can also activate or inactivate cytokines and thereby regulate cardiac inflammation. During the transition from the acute to the chronic phase of myocarditis, a tightly regulated balance between pro- and anti-inflammatory signalling is critical. Disruption of this balance may lead to exaggerated immune responses or viral persistence. During acute myocarditis, infiltrated immune cells form foci of inflammation that are consistently co-localized with areas of fibrosis. Interestingly, the fibrotic response accompanying cardiac inflammation during the acute phase is reversible following resolution of inflammation. This project aims to investigate the role of MMPs in facilitating immune cell invasion during myocarditis, to elucidate the pathophysiological mechanisms underlying fibrosis resolution, and to explore the biological activity of ECM-derived cleavage products in modulating inflammation during the recovery phase.
Thesis topic 2: Cell-specific function of viral proteases 3CPro and 2APro during virus-mediated and persistence myocarditis
In the heart, Coxsackievirus B3 (CVB3) infects various cardiac cell types, including cardiomyocytes and cardiac fibroblasts. Its RNA genome encodes two viral proteases, 3CPro and 2APro, which mediate proteolytic cleavage of host proteins upon infection. These protease-driven alterations can disrupt essential cellular functions, especially during viral persistence, where ongoing, subclinical protease activity may contribute to the gradually deterioration of cardiac function. This project aims to identify cell type–specific intracellular substrates of the viral proteases and to compare the proteolytic activity of 3CPro and 2APro in the two most affected cardiac cell types. Additionally, these protease-driven alterations will be compared to those observed in myocarditis induced by native CVB3 infection.