The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo

Abstract

Effective mucosal adjuvants enhance the magnitude and quality of the vaccine response. Cyclic di-GMP (CDG) is a promising mucosal vaccine adjuvant. However, its in vivo mechanisms are unclear. Here, we showed, in mice, that CDG elicits stronger Ab and TH responses than the mammalian 2′3′-cyclic GMP-AMP (cGAMP), and generated better protection against Streptococcus pneumoniae infection than 2′3′-cGAMP adjuvanted vaccine. We identified two in vivo mechanisms of CDG. First, intranasally administered CDG greatly enhances Ag uptake, including pinocytosis and receptor-mediated endocytosis in vivo. The enhancement depends on MPYS (STING, MITA) expression in CD11C+ cells. Second, we found that CDG selectively activated pinocytosis-efficient-DCs, leading to TH polarizing cytokines IL-12p70, IFNγ, IL-5, IL-13, IL-23, and IL-6 production in vivo. Notably, CDG induces IFNλ, but not IFNβ, in vivo. Our study revealed previously unrecognized in vivo functions of MPYS and advanced our understanding of CDG as a mucosal vaccine adjuvant.DOI: http://dx.doi.org/10.7554/eLife.06670.001

The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele

“…MPYS is a cytosolic sensor for cyclic dinucleotides (CDNs) including bacterial CDNs, cyclic di-AMP (CDA), cyclic di-GMP (CDG), and mammalian CDN 2′5′-3′5′-cyclic GMP-AMP (2′3′-cGAMP) generated during cytosolic DNA sensing(4–6). Consequently, MPYS is critical for host defense against DNA viruses(7), RNA viruses(7, 8), intracellular bacteria(9, 10) and extracellular bacteria(11, 12) in mice. MPYS also plays a key role in the development of auto-inflammatory diseases in mice(13–15) and STING-associated vasculopathy with onset in infancy (SAVI) in humans(16, 17).…”

The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons

“…vaccination, mice were immunized on days 0 and 14 with PspA (2 µg, BEI Resources) alone, or in combination with chitosan (50 µg), as previously described (Blaauboer et al, 2015). Briefly, animals were anaesthetized using isoflurane in an E-Z Anesthesia system (Euthanex Corp).…”

Natural STING Agonist as an “Ideal” Adjuvant for Cutaneous Vaccination

“…The adjuvant effect of cGAMP has been demonstrated in mice by co-injection cGAMP and ovalbumin, a model protein vaccine, into the muscle (Li et al, 2013). Its bacterial analog, cyclic di-GMP (cdGMP) has been studied extensively as a potential vaccine adjuvant for bacteria vaccines through IM, subcutaneous, intraperitoneal or intranasal vaccinations (Karaolis et al, 2007, Ogunniyi et al, 2008, Ebensen et al, 2007a, Ebensen et al, 2007b, Blaauboer et al, 2015). Recently, modified nonhydrolyzable cGAMP analogs have also been shown to have potent anti-tumor activity when administered intratumorally (Corrales et al, 2015).…”