Cyclic Di-GMP Signaling and Host Immunity

Testing the hypothesis that cyclic Di-GMP (c-di-GMP) can be used clinically to inhibit infection, synthetic exogenous c-di-GMP was found not to be bactericidal or bacteriostatic but could significantly inhibit Staphylococcus aureus biofilm formation in vitro. Subsequent studies have clearly shown that c-di-GMP exerts important immunomodulatory effects on host immune cells that participate in antibacterial immunity. The generation of acquired immunity is necessary for effective cellular and humoral responses to invading pathogens. Dendritic cells (DC) are the most potent antigen-presenting cells and are integrated within mucosal surfaces, where they are well positioned to survey antigens. The higher antibody titer produced suggests that c-di-GMP (and its analogs) can be used instead of alum as an immune modulator or vaccine adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive and systemic disease and that c-di-GMP can be used as an effective broad-spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases. The mechanism of internalization is uncertain, but passive diffusion, rather than active transport, is thought to be the most likely route. While the functional significance of naturally bacterium-derived c-di-GMP in regulating immunological response is largely untested, based on data from numerous in vivo and in vitro models, it is clear that c-di-GMP has drug-like properties and can affect host immunity.