Antigen Localization Influences the Magnitude and Kinetics of Endogenous Adaptive Immune Response to Recombinant Salmonella Vaccines.
Antigen Localization Influences the Magnitude and Kinetics of Endogenous Adaptive Immune Response to Recombinant Salmonella Vaccines.
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DOI：
10.1128/iai.00593-17
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发表时间：
2017-12
影响因子：
3.1
通讯作者：
Rossiter AE
中科院分区：
文献类型：
--
作者：
Sevastsyanovich YR;Withers DR;Marriott CL;Morris FC;Wells TJ;Browning DF;Beriotto I;Ross E;Ali HO;Wardius CA;Cunningham AF;Henderson IR;Rossiter AE
使用重组减毒沙门氏菌疫苗（RASV）菌株是一种向哺乳动物免疫系统呈递异源抗原以诱导细胞和体液免疫反应的有前途的策略。然而，关于RASV发育的研究对于异源抗原在细菌内表达和定位的位置存在不同，并且目前还不清楚抗原定位如何调节免疫反应。此前，我们利用质粒编码毒素（Pet）自转运系统在细胞培养上清液中积累异源抗原。在本研究中，该 Pet 系统用于在肠沙门氏菌鼠伤寒沙门氏菌菌株 SL3261 中表达早期分泌抗原 6 (ESAT-6)，这是一种来自结核分枝杆菌的免疫显性和诊断抗原。产生了三种菌株，其中ESAT-6表达为细胞质（SL3261/细胞）、表面结合（SL3261/surf）或分泌（SL3261/秒）抗原。使用这些RASV，系统地检查了受感染的C57BL/6小鼠中抗原定位和免疫原性之间的关系。使用纯化的抗原和特异性四聚体，我们发现与感染 SL3261/cyto 的小鼠相比，感染 SL3261/surf 或 SL3261/sec 菌株的小鼠产生大量 Th1 CD4+ ESAT-6+ 脾 T 细胞。虽然所有小鼠在感染 SL3261/surf 或 SL3261/秒时均表现出 ESAT-6 特异性抗体反应，但接受 SL3261/秒的小鼠更快地达到总血清 IgG 抗体滴度峰值。因此，抗原在细菌内产生后如何定位对抗体反应的影响比对 CD4+ T 细胞反应的影响更显着，这可能会影响在 RASV 中定位重组抗原的策略的选择。
The use of recombinant attenuated Salmonella vaccine (RASV) strains is a promising strategy for presenting heterologous antigens to the mammalian immune system to induce both cellular and humoral immune responses. However, studies on RASV development differ on where heterologous antigens are expressed and localized within the bacterium, and it is unclear how antigen localization modulates the immune response. Previously, we exploited the plasmid-encoded toxin (Pet) autotransporter system for accumulation of heterologous antigens in cell culture supernatant. In the present study, this Pet system was used to express early secretory antigen 6 (ESAT-6), an immunodominant and diagnostic antigen from Mycobacterium tuberculosis, in Salmonella enterica serovar Typhimurium strain SL3261. Three strains were generated, whereby ESAT-6 was expressed as a cytoplasmic (SL3261/cyto), surface-bound (SL3261/surf), or secreted (SL3261/sec) antigen. Using these RASVs, the relationship between antigen localization and immunogenicity in infected C57BL/6 mice was systematically examined. Using purified antigen and specific tetramers, we showed that mice infected with the SL3261/surf or SL3261/sec strain generated large numbers of Th1 CD4+ ESAT-6+ splenic T cells compared to those of mice infected with SL3261/cyto. While all mice showed ESAT-6-specific antibody responses when infected with SL3261/surf or SL3261/sec, peak total serum IgG antibody titers were reached more rapidly in mice that received SL3261/sec. Thus, how antigen is localized after production within bacteria has a more marked effect on the antibody response than on the CD4+ T cell response, which might influence the chosen strategy to localize recombinant antigen in RASVs.
影响因子：
6.4
作者：
Zhang J;De Masi L;John B;Chen W;Schifferli DM
通讯作者：
Schifferli DM