Abstract
The recently discovered mammalian enzyme cyclic GMP-AMP synthase produces cyclic GMP-AMP (cGAMP) after being activated by pathogen-derived cytosolic double stranded DNA. The product can stimulate STING-dependent interferon type I signaling. Here, we explore the efficacy of cGAMP as a mucosal adjuvant in mice. We show that cGAMP can enhance the adaptive immune response to the model antigen ovalbumin. It promotes antigen specific IgG and a balanced Th1/Th2 lymphocyte response in immunized mice. A characteristic of the cGAMP-induced immune response is the slightly reduced induction of interleukin-17 as a hallmark of Th17 activity – a distinct feature that is not observed with other cyclic di-nucleotide adjuvants. We further characterize the innate immune stimulation activity in vitro on murine bone marrow-derived dendritic cells and human dendritic cells. The observed results suggest the consideration of cGAMP as a candidate mucosal adjuvant for human vaccines.
Highlights
Cyclic di-nucleotides (CDNs) are bacterial second messengers with functions in motility and development
For mucosal vaccination, for example via the nasal route, adjuvants need to be suited to cross the mucosal barrier but at the same time have to meet high safety standards. Molecules such as cyclic GMP-AMP (cGAMP) that are produced by the mammalian organism itself are expected to be of very low toxicity
We demonstrate the efficacy of cGAMP as an i. n. administered mucosal adjuvant in a pre-clinical mouse model
Summary
Cyclic di-nucleotides (CDNs) are bacterial second messengers with functions in motility and development. Bis-(39,59)-cyclic dimeric guanosine monophosphate (c-di-GMP), a member of this molecule family, is produced for example by the bacterium Pseudomonas aeruginosa in which it functions in biofilm formation [1,2]. Immunization experiments on mice using CDNs as adjuvants suggest that they can have the immune activity of pathogen associated molecular patterns (PAMPs). C-di-GMP, c-diAMP, and the non-natural bis-(39,59)-cyclic dimeric inosine monophosphate were shown by us and others to have immune stimulatory effects and to promote balanced specific humoral and cellular responses upon immunization of mice [7,8,9,10]
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