Abstract
The recurrent Coxsackievirus B3 (CVB3) infection is the most important cause of intractable myocarditis which often leads to chronic myocarditis and even dilated cardiomyopathy. Therefore, enhanced DNA vaccines capable of memory CD8 T cells are essential for long-lasting immunological protection against CVB3 infection. In this study, absent in melanoma 2 (AIM2) was used as an adjuvant to enhance the induction of memory CD8 T cells elicited by VP1 (viral capsid protein 1) vaccine. Mice were intramuscularly injected with 50 μg AIM2 plasmid and equal amount of VP1 plasmid (pAIM2/pVP1) vaccine 4 times at 2 week-intervals. We observed that the protection of pAIM2/pVP1 vaccine against CVB3 challenge was evidenced by significantly improved cardiac function, reduced myocardial injuries, and increased survival rate when compared with immunization with pVP1. Co-immunization with pAIM2/pVP1 robustly augmented T lymphocytes proliferation and CVB3-specific cytotoxic T lymphocyte responses. Importantly, 16 weeks after the last immunization, pAIM2/pVP1 co-immunization significantly enhanced the expression of Bcl-6, SOCS3, and Sca-1 which are critical for memory CD8 T cells as compared with pVP1 immunization. Notably, CD8 T cells that are likely vaccine-induced memory T cells were responsible for the protective efficacy of pAIM2/pVP1 vaccine by abolition of a CD8 T cell immune response following a lethal dose of CVB3 infection. Our results indicate that AIM2-adjuvanted vaccine could be a potential and promising approach to promote a long-lasting protection against CVB3-induced myocarditis.
Highlights
Coxsackievirus B3 (CVB3) is one of non-enveloped, positive-sense, single-stranded RNA viruses and it is a principle etiologic agent in myocarditis (Palmenberg, 1990; Tam, 2006; Bailey and Tapprich, 2007)
To explore the long-lasting protection efficacy of pAIM2/pVP1 vaccine, 16 weeks after the last immunization, groups of mice were intraperitoneally infected with a normal lethal dose of CVB3 (3LD50/mouse) for the induction of acute myocarditis
Histological analysis of hematoxylin and eosin (HE)-stained heart sections showed that tiny areas of myocytes necrosis and infiltrating inflammatory cells were observed in pAIM2/pVP1
Summary
Coxsackievirus B3 (CVB3) is one of non-enveloped, positive-sense, single-stranded RNA viruses and it is a principle etiologic agent in myocarditis (Palmenberg, 1990; Tam, 2006; Bailey and Tapprich, 2007). Vaccination strategies are able to induce potent memory T cells immune responses that are likely to be the most successful in preventing the subsequent CVB3 infection and progression to chronic myocarditis or dilated cardiomyopathy (Henke et al, 2001; Maisch and Pankuweit, 2012; Griffiths and Khader, 2014). DNA sensor AIM2 could act as a mucosal adjuvant for VP1 vaccine to induce mucosal immune responses against CVB3 challenge (Chai et al, 2014). A more recent study showed that Mycobacterium bovis BCG heterologously expressing the esx-1 region of Mycobacterium marinum induces the cGAS/STING/TBK1/IRF3/type I interferon axis and enhances AIM2 and NLRP3 inflammasome activity, resulting in both higher proportions of CD8 T cell effectors against mycobacterial antigens and polyfunctional CD4+ Th1 cells, further suggesting the role of AIM2 as a sensor for DNA vaccines. Whether AIM2 enhance memory CD8 T cell immune responses by VP1 intramuscular vaccine remains unclear
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