T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.
T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins.
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全细胞疫苗对 T(H)17 介导的肺炎球菌携带保护依赖于 Toll 样受体 2 和表面脂蛋白。
DOI：
10.1128/cvi.00118-15
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Malley,R
中科院分区：
文献类型：
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作者：
Moffitt,K;Howard,A;Martin,S;Cheung,E;Herd,M;Basset,A;Malley,R
肺炎球菌全细胞疫苗（WCV）赋予TH 17介导的免疫原性并减少小鼠中的鼻咽（NP）携带。Toll样受体2（TLR 2）的激活已被证明对于产生TH 17应答是重要的，并且几种脂化的肺炎球菌蛋白具有TLR 2激活特性。在这里，我们研究了TLR 2和脂质化的蛋白质在WCV诱导的白细胞介素-17A（IL-17 A）的反应和保护对NP运载的作用。与野生型（WT）小鼠相比，用WCV免疫Tlr 2 −/−小鼠可显著降低IL-17 A水平并降低对NP携带的保护，这表明宿主TLR 2参与是WCV免疫引起的有效免疫和保护所必需的。使用WCV缺失oflgt，基因编码的酶所需的脂化和膜附着的前脂蛋白，我们表明，这些蛋白质的脂化和膜定位的免疫原性和保护效力的WCV是至关重要的。为了评估二酰基甘油基转移酶（Lgt）介导的过程在回忆WCV诱导的保护性反应中的作用，我们用Lgt缺失的菌株定殖WCV免疫的动物。与对照动物相比，WCV免疫的动物仍然具有显著降低的定殖负担，这表明肺炎球菌前脂蛋白的脂化和膜定位对于WCV免疫引起的免疫应答的回忆比对于引发这种应答的回忆不那么重要。阐明潜在的免疫机制和WCV制剂的最佳特性可以帮助指导疫苗开发并增强我们对宿主-肺炎球菌相互作用的理解。
A pneumococcal whole-cell vaccine (WCV) confers TH17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating TH17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization ofTlr2−/−mice with WCV conferred significantly lower IL-17A levels and reduced protection against NP carriage, compared to wild-type (WT) mice, suggesting that host TLR2 engagement is required for effective immunity and protection elicited by WCV immunization. Using a WCV with deletion oflgt, the gene encoding the enzyme required for lipidation and membrane attachment of prolipoproteins, we show that lipidation and membrane localization of these proteins are critical for the immunogenicity and protective efficacy of the WCV. To evaluate the roles of diacylglyceryl transferase (Lgt)-mediated processes in the recall of WCV-induced protective responses, we colonized WCV-immunized animals with a strain in whichlgtwas deleted. WCV-immunized animals still had significantly reduced colonization burdens, compared to control animals, which suggests that lipidation and membrane localization of pneumococcal prolipoproteins are less critical for the recall of the immune responses elicited by WCV immunization than for the priming of such responses. Elucidation of underlying immune mechanisms and the optimal characteristics of WCV formulations can help guide vaccine development and enhance our understanding of host-pneumococcus interactions.