Protease-Activated Receptor-2 Regulates the Innate Immune Response to Viral Infection in a Coxsackievirus B3–Induced Myocarditis
Key result
PAR2 knockout prevents murine viral myocarditis, while human expression links to inflammation and reduced LVEF.
Why the study?
This study sought to evaluate the role of protease-activated receptor-2 in coxsackievirus B3-induced myocarditis.
Does PAR2 knockout reduce viral replication and prevent myocarditis in CVB3-infected mice?
Key Points
- This research aims to evaluate the role of PAR2 in the immune response to CVB3-induced myocarditis.
- Infected wild-type and PAR2 knockout mice with CVB3 to induce myocarditis.
- Analyzed hearts and cardiac cells using plaque assays, qPCR, Western blot, and immunohistochemistry.
- Measured hemodynamic function with a 1.2-F microconductance catheter.
- PAR2 knockout mice exhibited reduced viral load and no myocarditis after CVB3 infection.
- IFNβ expression was higher in PAR2 knockout hearts and fibroblasts compared to wild-type.
- Overexpression of PAR2 reduced baseline IFNβ levels, indicating a negative regulation.
Structured PICO
Does PAR2 knockout reduce viral replication and prevent myocarditis in CVB3-infected mice?
P
Population
Wild-type and PAR2 knockout mice infected with CVB3, alongside endomyocardial biopsies from patients with nonischemic cardiomyopathy.
E
Exposure
Infection with 10^5 plaque-forming units coxsackievirus B3 (CVB3)
C
Comparator
Wild-type mice compared to PAR2 knockout mice
O
Outcome
Viral replication and immune response (myocarditis development, IFNβ expression)surrogate
PAR2 negatively regulates the innate immune response to CVB3 infection, suggesting PAR2 antagonism may be a therapeutic target for viral myocarditis.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Interestingly, we found that PAR1 knockout mice had increased cardiac injury whereas PAR2 knockout mice had decreased cardiac injury. Our studies support the notion that PARs modulate the innate immune response and can have both positive and negative effects on TLR-dependent responses.”
“Considerable progress has been made at the basic research level in our understanding of the molecular pathophysiology of myocarditis, as exemplified by the eloquent report of Weithauser et al. in this issue of the Journal.”
Implication
PAR2 inhibition may mitigate viral myocarditis in mice; leaves open translation to human disease.
Abstract
This study sought to evaluate the role of protease-activated receptor-2 (PAR2) in coxsackievirus B3 (CVB3)–induced myocarditis. An infection with CVB3 leads to myocarditis. PAR2 modulates the innate immune response. Toll-like receptor-3 (TLR3) is crucial for the innate immune response by inducing the expression of the antiviral cytokine interferon-beta (IFNβ). To induce myocarditis, wild-type (wt) and PAR2 knockout (ko) mice were infected with 10 5 plaque-forming units CVB3. Mice underwent hemodynamic measurements with a 1.2-F microconductance catheter. Wt and PAR2ko hearts and cardiac cells were analyzed for viral replication and immune response with plaque assay, quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Compared with wt mice, PAR2ko mice and cardiomyocytes exhibited a reduced viral load and developed no myocarditis after infection with CVB3. Hearts and cardiac fibroblasts from PAR2ko mice expressed higher basal levels of IFNβ than wt mice did. Treatment with CVB3 and polyinosinic:polycytidylic acid led to higher IFNβ expression in PAR2ko than in wt fibroblasts and reduced virus replication in PAR2ko fibroblasts was abrogated by neutralizing IFNβ antibody. Overexpression of PAR2 reduced the basal IFNβ expression. Moreover, a direct interaction between PAR2 and Toll-like receptor 3 was observed. PAR2 expression in endomyocardial biopsies of patients with nonischemic cardiomyopathy was positively correlated with myocardial inflammation and negatively with IFNβ expression and left ventricular ejection fraction. PAR2 negatively regulates the innate immune response to CVB3 infection and contributes to myocardial dysfunction. The antagonism of PAR2 is of therapeutic interest to strengthen the antiviral response after an infection with a cardiotropic virus.
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Cite This Study
Weithäuser et al. (2013) studied Coxsackievirus B3-induced myocarditis. PAR2 knockout / PAR2 expression vs. Wild-type / lower PAR2 expression was evaluated on Viral load and myocarditis development. PAR2 knockout mice exhibited reduced viral load and developed no myocarditis after CVB3 infection, and PAR2 expression in patients correlated with myocardial inflammation and reduced LVEF.