| Infectious diseases continue to be the most serious threat to the public health. In fact, over sixty percentages of infectious diseases are caused by viral infections and hepatitis B are the highest incidence of infectious diseases in China. At present, there are over nine percentages of the population are infected with HBV and over200,000people died from HBV-related diseases each year. Since March2013, we had confirmed over419cases infected with newly-emerged H7N9avian influenza virus, with127deads. The high mortality rates and pandemic potentials threaten the social security and people’s health. However, there are still no preferred preventions and treatment against viral infections. Therefore, investigations on developing novel therapeutic strategies have great significant for the prevention and control of viral infectious diseases.DNA vaccine has a great potential to be used for the treatment of chronic HBV infection, owing to their advantage in stimulating both humoral immune responses and cellular immune responses. However, it drives significantly weaker immune responses in non-human primates and in humans compared with mice. Previously, we have shown that either cimetidine or praziquantel could enhance the therapeutic effects of HBV DNA vaccine through different pathways. The primary objectives of this study were to confirm whether cimetidine could synergize with praziquantel to enhance the immune response of HBV DNA vaccine. Here we show that combination of CIM and PZQ as adjuvants for a HBV DNA vaccine could not only significantly reduce the number and function of CD4+CD25+Foxp3+Tregs. In addition, the HBsAg-specific cytotoxic CD8+T cell was also elevated significantly, which is critical for the eradication of HBV infected cells. Further investigations demonstrated that the cytotoxic function of activated CD8+T cells was dependent on the expression of IFN-y and IL-17A. Using a HBsAg transgenic mouse model, the expression of HBsAg in the hepatic cells was also significantly reduced after immunized with pCD-S2in the presence of0.5%of CIM and0.25%of PZQ. Therefore, relative safety records for CIM and PZQ could make them as effective adjuvants for the development of therapeutic vaccines against chronic viral infections.IL-17A is a newly-defined cytokine, mainly produced by Th17cells and considered to be a potent mediator to bridge innate and adaptive immune systems. Recently, IL-17A has been demonstrated to be involved in several autoimmune diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, and Crohn’s diseases. Several investigations have reported the protective role of IL-17A in animal models of PR8influenza infection since neutralization of IL-17A in mice increases weight loss and reduces survival. This led us a great interest to investigate the protective role of IL-17A against H7N9virus infection and its mechanism. Here we analyzed the levels of different cytokines in the serum samples from patients infected with different influenza viruses and found that elevated serum levels of IL-17A are apparently associated with less severe disease in the H7N9-infected patients. Using an H7N9influenza virus infected mice model, we further confirmed that pre-administration with IL-17A could protect mice against lethal H7N9virus infection, the protective effects of IL-17A seems to be dependent on the secretion of IFN-y, an important host factor for viral clearance. In addition, IL-17A could also activate CD8+T cells isolated from healthy individuals’ blood in vitro and upregulate the secretion of IFN-γ. Together, these findings reveal that IL-17A plays pivotal roles in hosts against lethal H7N9virus infection, provide us with new ideas on developing IL-17A based strategy to combat the emerging lethal Influenza viruses and give a new direction for developing anti-viral drugs. |
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