3′,5′-Cyclic diguanylic acid elicits mucosal immunity against bacterial infection

Yan, Hongbin; KuoLee, Rhonda; Tram, Kha; Qiu, Hongyu; Zhang, Jianbing; Patel, G. B.; Chen, Wangxue

doi:10.1016/j.bbrc.2009.07.061

Cited by 50 publications

(72 citation statements)

References 19 publications

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“…Recently, several groups have attempted to use c-di-GMP to prevent bacterial infections [14,[18][19][20][21][22][23], problems were encountered when c-di-GMP was used as a drug. C-di-GMP contains two phosphate groups and this prevents it from passing through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm [24].…”

Section: Introductionmentioning

confidence: 99%

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Miyabe

Hyodo

Nakamura

et al. 2014

Journal of Controlled Release

139

108

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Cyclic dinucleotides are of importance in the field of microbiology and immunology. They function as second messengers and are thought to participate in the signal transduction of cytosolic DNA immune responses. One such dinucleotide, cyclic di-GMP (c-di-GMP), stimulates the immune system. C-di-GMP is thought to be recognized by ATP dependant RNA helicase (DDX41) in the cytosol, forms a complex with the Stimulator of interferon genes protein (STING), triggers the signal via the tank binding kinase 1 -interferon regulatory factor 3 (TBK1-IRF3) pathway and induces the production of type I interferons. Therefore c-di-GMP can be thought of as a new class of adjuvant. However, because c-di-GMP contains two phosphate groups, this prevents its use as the adjuvant because it cannot pass through the cell membrane, even though the target molecule of c-di-GMP is located in the cytoplasm.Our group have been developing a series of liposomal drug delivery systems and recently investigated YSK05 which is a synthetic lipid with a pH sensitivity and has a high fusogenicity. We utilized this lipid as a carrier to send c-di-GMP into the cytosol to then use c-di-GMP as an adjuvant. Based on screening experiments, YSK05/POPE/Cholesterol = 40/30/30 was found to induce IFN-β in Raw264.7 cells. The induction of IFN-β from c-di-GMP liposomes was inhibited by adding BX795, a TBK1 inhibitor, indicating that the production of IFN-β caused the activation of STING-TBK1 pathway. C-di-GMP liposomes also showed significantly higher levels of expression of CD80, CD86 and MHC class I. The c-di-GMP/YSK05 liposome facilitated antigen specific cytotoxic T cell activity and the inhibition of tumor growth in a mouse model. These findings indicate that c-di-GMP/YSK05 liposomes could be used, not only to transfer c-di-GMP to the cytosol and induce an innate immune system but also as a platform for investigating the mechanism of immune sensing with cyclic dinucleotides in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Miyabe

Hyodo

Nakamura

et al. 2014

Journal of Controlled Release

139

108

View full text Add to dashboard Cite

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“…immunized with PsaA/CT. 69 This result is very encouraging since CT is one of the most potent experimental mucosal adjuvants, and is considered the "gold standard" for mucosal adjuvants. However, due to its considerable toxicity to humans, CT is not approved for human vaccination.…”

Section: Exploitation Of Bacterial Ab 5 Toxins As Mucosal Adjuvantsmentioning

confidence: 84%

“…or i.n. instillation of c-di-GMP in mice induces the recruitment of monocytes, granulocytes and DCs at the application sites, 68,69 enhanced CD40 and CD86 expression in CD11c hi MHCII hi DCs, 70,71 and a dose-dependent induction of several key proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid. 71 More importantly, mouse models of several bacterial infections (Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae) have demonstrated that i.n.…”

Section: Potential Of C-di-gmp As a Mucosal Adjuvantmentioning

confidence: 98%

“…75 More recent work in our laboratories have extended these findings and demonstrated for the first time that the mucosal immune responses induced with c-di-GMP-adjuvanted vaccines generate protective immunity against pathogen challenge. 69 Mice intranasally immunized with pneumococcal surface adhesin A (PsaA) admixed with c-di-GMP induced antigen-specific IgA responses locally (bronchoalveolar space) and distally (feces) as well as serum IgG1 and IgG2a responses. As observed with mucosal immunization of β-Gal adjuvanted with c-di-GMP, 75 the serum anti-PsaA IgG2a levels in the immunized mice were higher than the IgG1 levels, suggesting a predominantly Th1 response.…”

Section: Exploitation Of Bacterial Ab 5 Toxins As Mucosal Adjuvantsmentioning

confidence: 99%

“…In addition, the mucosal and serum PsaA-specific antibodies were somewhat higher in PsaA/c-di-GMP immunized mice than in PsaA/cholera toxin (CT) immunized mice. 69 More importantly, upon i.n. challenge with S. pneumoniae, mice immunized with PsaA/c-di-GMP had significantly lower pathogen burdens in their nasal cavities compared to control groups immunized with PsaA alone, c-di-GMP alone, CT alone, or saline.…”

Section: Exploitation Of Bacterial Ab 5 Toxins As Mucosal Adjuvantsmentioning

confidence: 99%

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Recent advances in the development of novel mucosal adjuvants and antigen delivery systems

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Modern Subunit Vaccines: Development, Components, and Research Opportunities

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Traditional vaccines, based on the administration of killed or attenuated microorganisms, have proven to be among the most effective methods for disease prevention. Safety issues related to administering these complex mixtures, however, prevent their universal application. Through identification of the microbial components responsible for protective immunity, vaccine formulations can be simplified, enabling molecular-level vaccine characterization, improved safety profiles, prospects to develop new high-priority vaccines (e.g. for HIV, tuberculosis, and malaria), and the opportunity for extensive vaccine component optimization. This subunit approach, however, comes at the expense of decreased immunity, requiring the addition of immunostimulatory agents (adjuvants). As few adjuvants are currently used in licensed vaccines, adjuvant development represents an exciting area for medicinal chemists to play a role in the future of vaccine development. In addition, immune responses can be further customized though optimization of delivery systems, tuning the size of particulate vaccines, targeting specific cells of the immune system (e.g. dendritic cells), and adding components to aid vaccine efficacy in whole immunized populations (e.g. promiscuous T-helper epitopes). Herein we review the current state of the art and future direction in subunit vaccine development, with a focus on the described components and their potential to steer the immune response toward a desired response.

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3′,5′-Cyclic diguanylic acid elicits mucosal immunity against bacterial infection

Cited by 50 publications

References 19 publications

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

Recent advances in the development of novel mucosal adjuvants and antigen delivery systems

Modern Subunit Vaccines: Development, Components, and Research Opportunities

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