Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins.
Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins.
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DOI：
10.1016/j.vaccine.2017.02.064
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发表时间：
2017-04-25
期刊：
影响因子：
5.5
通讯作者：
Boyaka PN
中科院分区：
文献类型：
--
作者：
Martin TL;Jee J;Kim E;Steiner HE;Cormet-Boyaka E;Boyaka PN
炭疽病是由炭疽芽孢杆菌引起的，炭疽杆菌是一种影响世界各地人畜的人畜共患病细菌病原体。目前的人用炭疽疫苗，即吸附炭疽疫苗(AVA)，是一种注射疫苗，给药程序繁琐，无法促进粘膜免疫。细菌肠毒素可以刺激环核苷酸cAMP的产生，是有效的实验性黏膜疫苗佐剂，但其固有的毒性使其无法在人类身上使用。我们研究了哺乳动物细胞中以干扰素-γ基因刺激物(STING)为靶点的环二核苷酸是否可以替代细菌肠毒素作为舌下免疫佐剂，除全身免疫外，还能促进粘膜免疫和分泌型IgA反应。我们发现，炭疽杆菌保护性抗原(PA)和刺激性配体3‘3’-cGAMP舌下免疫小鼠可促进PA特异性的血清抗体应答，与PA和实验佐剂霍乱毒素(CT)免疫后的水平相同。有趣的是，这种刺激性配体还促进了血清中抗PA-IgA和骨髓中产生IgA的细胞。此外，以刺痛配体免疫的小鼠唾液中PA特异性IgA抗体水平与以CT为佐剂的免疫组相似。3‘3’-cGAMP的佐剂活性与Th1、Th2和Th17的混合应答有关。该刺激物还能在舌下组织和颈淋巴中诱导快速的干扰素-β和IL-10反应，在颈淋巴中诱导转化生长因子-β反应，这可能有助于促进舌下免疫后的免疫应答。
Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3′3′-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvants cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3′3′-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-β and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-β responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization.
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影响因子：
5.4
作者：
Bhat N;Fitzgerald KA
通讯作者：
Fitzgerald KA
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li XD;Wu J;Gao D;Wang H;Sun L;Chen ZJ
通讯作者：
Chen ZJ
DOI：
10.4049/jimmunol.0803740
发表时间：
2009-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cuburu N;Kweon MN;Hervouet C;Cha HR;Pang YY;Holmgren J;Stadler K;Schiller JT;Anjuère F;Czerkinsky C
通讯作者：
Czerkinsky C
DOI：
10.3390/v3060906
发表时间：
2011-06
期刊：
Viruses
影响因子：
--
作者：
Ireton RC;Gale M Jr
通讯作者：
Gale M Jr
影响因子：
17.1
作者：
Fu J;Kanne DB;Leong M;Glickman LH;McWhirter SM;Lemmens E;Mechette K;Leong JJ;Lauer P;Liu W;Sivick KE;Zeng Q;Soares KC;Zheng L;Portnoy DA;Woodward JJ;Pardoll DM;Dubensky TW Jr;Kim Y
通讯作者：
Kim Y