DNA vaccine combinations expressing either tissue plasminogen activator signal sequence fusion proteins or ubiquitin-conjugated antigens induce sustained protective immunity in a mouse model of pulmonary tuberculosis
DNA vaccine combinations expressing either tissue plasminogen activator signal sequence fusion proteins or ubiquitin-conjugated antigens induce sustained protective immunity in a mouse model of pulmonary tuberculosis
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DOI：
10.1128/iai.70.1.292-302.2002
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发表时间：
2002-01-01
影响因子：
3.1
通讯作者：
Morris, SL
中科院分区：
文献类型：
--
作者：
Delogu, G;Li, A;Morris, SL
DNA 疫苗接种已成为寻找更有效的结核病疫苗的有力方法。在这项研究中，我们评估了 10 种不同结核病 DNA 疫苗组合免疫的有效性，这些疫苗表达了 N 末端与真核细胞内靶向序列融合的分枝杆菌蛋白。在一种疫苗组合中，基因与组织纤溶酶原激活信号序列 (TPA) 融合，而在第二种组合中，相同的 10 个基因表达为泛素 (Ub) 结合蛋白。在测量γ干扰素分泌的离体研究中，在低剂量结核分枝杆菌攻击后7天和14天接种TPA DNA疫苗组合或Ub DNA疫苗组合的小鼠中检测到细胞免疫反应。此外，接种 TPA 组合、Ub 组合和牛分枝杆菌 BCG 疫苗的小鼠在受到剧毒结核气溶胶攻击后能够限制肺和脾中结核杆菌的生长。组织病理学分析还表明，相对于初始对照组，用 DNA 疫苗组合免疫的小鼠感染后肺部病理学得到了显着改善。最后，在三个不同的长期实验中，与未经处理的对照组相比，接种疫苗的小鼠在有气攻击后的存活期延长了七倍。有趣的是，在所有三个实验中，相对于 BCG 对照，用 TPA 组合或 Ub 组合免疫的小鼠的平均死亡时间没有检测到显着差异。总之，这些研究证明了 DNA 疫苗组合免疫对结核病的有效性，并表明有必要对这些质粒混合物进行进一步测试。
DNA vaccination has emerged as a powerful approach in the search for a more efficacious vaccine against tuberculosis. In this study, we evaluated the effectiveness of immunizing with combinations of 10 different tuberculosis DNA vaccines that expressed mycobacterial proteins fused at the N terminus to eukaryotic intracellular targeting sequences. In one vaccine combination, the genes were fused to the tissue plasminogen activator signal sequence (TPA), while in a second combination the same 10 genes were expressed as ubiquitin (Ub)-conjugated proteins. In ex vivo studies in which the secretion of gamma interferon was measured, cellular immune responses were detected in mice vaccinated with either the TPA DNA vaccine combination or the Ub DNA vaccine combination at 7 and 14 days following a low-dose Mycobacterium tuberculosis challenge. Moreover, mice vaccinated with the TPA combination, the Ub combination, and Mycobacterium bovis BCG were able to limit the growth of tubercle bacilli in the lung and spleen after a virulent tuberculous aerosol challenge. Histopathological analyses also showed that mice immunized with the DNA vaccine combinations had substantially improved postinfection lung pathology relative to the naive controls. Finally, in three different long-term experiments, the survival periods following aerogenic challenge were extended as much as sevenfold for vaccinated mice compared to naive controls. Interestingly, in all three experiments, no significant differences were detected in the mean times to death for mice immunized with the TPA combination or the Ub combination relative to the BCG controls. In conclusion, these studies demonstrate the effectiveness of immunization with DNA vaccine combinations against tuberculosis and suggest that further testing of these plasmid cocktails is warranted.