Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity.
Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity.
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DOI：
10.1073/pnas.2102435118
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发表时间：
2021-08-24
影响因子：
11.1
通讯作者：
Boyaka PN
中科院分区：
文献类型：
--
作者：
Kim E;Attia Z;Woodfint RM;Zeng C;Kim SH;Steiner HE;Shukla RK;Liyanage NPM;Ghimire S;Li J;Renukaradhya GJ;Satoskar AR;Amer AO;Liu SL;Cormet-Boyaka E;Boyaka PN
我们报告了抑制丝氨酸蛋白酶弹性酶重塑由注射的含有明矾佐剂的疫苗所引起的先天反应。这种重新编程改善了血流中保护性抗体的诱导，并刺激了支持粘膜组织中抗体反应发展的天然信号。我们的发现确定弹性蛋白酶是钝化明矾佐剂活性的内在调节因子。他们还表明，通过粘膜途径接种疫苗并不是粘膜组织和分泌物中抗体反应的绝对要求。补充含有SARS-CoV-2刺突蛋白亚基1作为抗原的明矾疫苗可增加小鼠血液和粘膜分泌物中的抗SARS-CoV-2免疫。因此，这一策略可能有助于未来基于蛋白质的SARS-CoV-2疫苗的开发。明矾用作注射疫苗的佐剂，可促进辅助性T细胞2(Th2)和血清抗体(Ab)反应。然而，它不能诱导粘膜组织中分泌型免疫球蛋白(Ig)A(SIgA)，诱导Th1和细胞免疫效果差。明矾刺激白细胞介素1(IL-1)和包括中性粒细胞在内的髓系细胞的募集。我们调查了中性粒细胞弹性蛋白酶是否调节明矾的佐剂能力，以及针对中性粒细胞弹性蛋白酶的策略是否可以改善对注射疫苗的反应。联合使用弹性蛋白酶的药物抑制剂或缺乏弹性蛋白酶的小鼠，在用明矾吸附的蛋白疫苗免疫后，产生高亲和力的血清抗体，包括严重急性呼吸综合征冠状病毒2号(SARS-CoV-2)的刺突蛋白。这些小鼠还产生了更广泛的抗原特异性CD4+T细胞反应，包括高Th1和T滤泡辅助(TFH)反应。有趣的是，在没有弹性蛋白酶活性的情况下，以明矾为佐剂的系统免疫可诱导粘膜SIgA反应。重要的是，弹性蛋白酶活性的缺乏或抑制增加了抗SARS-CoV-2刺激性亚单位1(S1)抗体的数量，这些抗体与新冠肺炎患者血清中相同的刺激性1蛋白表位发生反应。因此，抑制中性粒细胞弹性蛋白酶可能是一种有吸引力的策略，以提高明矾注射疫苗诱导包括粘膜免疫在内的广泛免疫的效果。
We report that suppression of the serine protease elastase reshapes innate responses induced by injected vaccines containing alum adjuvant. This reprogramming improves the induction of protective antibodies in the bloodstream and stimulates innate signals, which support the development of antibody responses in mucosal tissues. Our findings identify elastase as the innate regulator that blunts the adjuvant activity of alum. They also demonstrate that vaccination via mucosal routes is not an absolute requirement for antibody responses in mucosal tissues and secretions. Supplementation of an alum-based vaccine containing SARS-CoV-2 spike protein subunit 1 as antigen increased anti–SARS-CoV-2 immunity in the blood and mucosal secretions in mice. Thus, this strategy could help in the development of future protein-based vaccines against SARS-CoV-2. Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti–SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity.
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DOI：
10.4049/jimmunol.1601775
发表时间：
2017-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Boyaka PN
通讯作者：
Boyaka PN
DOI：
10.4049/jimmunol.0900164
发表时间：
2009-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
McKee AS;Munks MW;MacLeod MK;Fleenor CJ;Van Rooijen N;Kappler JW;Marrack P
通讯作者：
Marrack P
DOI：
10.4049/jimmunol.1700354
发表时间：
2017-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bird AK;Chang M;Barnard J;Goldman BI;Meednu N;Rangel-Moreno J;Anolik JH
通讯作者：
Anolik JH
影响因子：
82.9
作者：
Flach, Tracy L.;Ng, Gilbert;Shi, Yan
通讯作者：
Shi, Yan
影响因子：
56.9
作者：
Jordan, MB;Mills, DM;Cambier, JC
通讯作者：
Cambier, JC