Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization
1Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, 199 Ren-Ai Road, Suzhou 215123, PR China.
Abstract:
Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, affects about 5-20% of the world population and lacks efficient treatments. We previously reported that monocyte chemotactic protein-1 (MCP-1, CCL2) was significantly induced during CVB3 infection and greatly contributed to the myocardic inflammation and injury. Herein a CCL2 mutant with removed chemotactic activity was administrated and its therapeutic effect on CVB3-induced myocarditis was explored. A dominant negative CCL2 mutant, lacking the N-terminal amino acids 2-8 (CCL2(Δ2-8)), was genetically constructed and intramuscularly injected into BALB/c mice after CVB3 infection, severity of myocarditis was evaluated by weight loss, survival rate, serological indices and pathological observation. Systemic and local Th1/Th2 cytokine profiles were also assessed. Mice receiving pCCL2(Δ2-8) exhibited a profound attenuation of myocarditis compared to pcDNA3.1 or non-treated mice, as evidenced by invariant body weight, decreased serum CK-MB level, reduced myocardial inflammatory infiltration and increased survival. This effect was not attributable to the efficient viral clearance, but associated with weakened Th1 immune responses, as evidenced by significantly reduced CD4(+)IFN-γ(+) T cell frequency and Th1 cytokine level systemically and locally. Strategy of blocking in vivo CCL2 activity could effectively alleviate the severity of CVB3-induced myocarditis and may present an alternative therapeutic approach against viral myocarditis.
Insights
Blocking monocyte chemotactic protein-1 (MCP-1, CCL2) activity with a mutant protein significantly reduced viral myocarditis severity in mice. This approach offers a potential new therapy for Coxsackievirus B3-induced heart inflammation.
Area of Science:
- Immunology
- Virology
- Cardiology
Background:
- Viral myocarditis, often caused by Coxsackievirus B3 (CVB3), impacts 5-20% of the global population with limited treatment options.
- Monocyte chemotactic protein-1 (MCP-1, also known as CCL2) is significantly induced during CVB3 infection and contributes to myocardial inflammation and injury.
Purpose of the Study:
- To investigate the therapeutic potential of a non-chemotactic CCL2 mutant in a mouse model of CVB3-induced myocarditis.
- To evaluate the impact of blocking CCL2 activity on disease severity, viral clearance, and immune responses.
Main Methods:
- A dominant-negative CCL2 mutant (CCL2(Δ2-8)) was constructed and administered intramuscularly to mice post-CVB3 infection.
- Myocarditis severity was assessed through body weight, survival rates, serum markers (e.g., CK-MB), and pathological examination.
- Systemic and local Th1/Th2 cytokine profiles and T cell responses (CD4(+)IFN-γ(+)) were analyzed.
Main Results:
- Mice treated with the CCL2 mutant showed significantly attenuated myocarditis, including stable body weight, reduced serum CK-MB, less myocardial inflammation, and improved survival compared to controls.
- The therapeutic effect was not linked to enhanced viral clearance but was associated with suppressed Th1 immune responses.
- Reduced CD4(+)IFN-γ(+) T cell frequency and lower levels of Th1 cytokines were observed both systemically and locally.
Conclusions:
- Blocking in vivo CCL2 activity effectively alleviates the severity of CVB3-induced myocarditis.
- This strategy presents a promising alternative therapeutic approach for viral myocarditis.
