Transcriptional and immunological analysis of the putative outer membrane protein and vaccine candidate TprL of Treponema pallidum.
Transcriptional and immunological analysis of the putative outer membrane protein and vaccine candidate TprL of Treponema pallidum.
复制标题
假定的外膜蛋白和疫苗候选tprl的转录和免疫学分析。
DOI：
10.1371/journal.pntd.0008812
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发表时间：
2021-01
影响因子：
3.8
通讯作者：
Giacani L
中科院分区：
文献类型：
--
作者：
Haynes AM;Fernandez M;Romeis E;Mitjà O;Konda KA;Vargas SK;Eguiluz M;Caceres CF;Klausner JD;Giacani L
一种有效的梅毒疫苗应能产生梅毒螺旋体亚种的抗体。梅毒螺旋体(梅毒螺旋体)表面抗原通过吞噬细胞来诱导病原体清除。尽管结合梅毒螺旋体的生物信息学、结构和功能分析来鉴定可能的外膜蛋白(OMP)，得出了一系列潜在的候选疫苗，但关于这些基因的转录是否以及如何在感染过程中受到调控，仍然知之甚少。这种知识差距是疫苗设计的一个限制，因为对一种抗原产生的免疫可以在转录水平下调甚至沉默，而不影响毒力，不会导致病原体清除，从而允许疾病进展。我们在这里报道了编码推测的OMP和疫苗候选TprL的梅毒螺旋体基因tp1031在几个梅毒螺旋体菌株中的差异表达，提示转录调控。对tprL转录起始点的实验鉴定表明，tprL启动子内存在一个长度可变的均聚体G序列，其长度影响启动子的活性，与时相变化相一致。相反，在关系密切的病原菌T.p.subsp.Pertenue是雅司氏菌的病原体，自然发生的缺失消除了tprL启动子区域、蛋白质合成所需的元件和部分基因ORF，与梅毒螺旋体相比，tprL转录水平可以忽略不计。因此，与感染梅毒的受试者相比，感染雅司病的实验动物和患者中缺乏对TprL的体液反应。梅毒螺旋体随机改变tprL表达的能力应该在任何包括这种抗原的疫苗开发工作中被考虑。阶段变化在梅毒螺旋体抗原多样性中的作用有待进一步研究。梅毒在许多低收入和中等收入国家仍然是一种地方病，近20年来在高收入国家死灰复燃。在流行地区，梅毒仍然在患者中造成显著的发病率和死亡率，特别是当其病原体梅毒螺旋体亚种时。梅毒在怀孕期间传播给胎儿。尽管美国正在努力寻找一种有效的梅毒疫苗，以便在十年内投入临床试验，但由于缺乏对许多候选疫苗编码基因转录调控的知识，这些努力受到了部分阻碍。在这里，我们开始解决这一知识空白的假定外膜蛋白(OMP)和疫苗候选TprL，由tp1031基因编码。正如我们之前报道的其他可能的梅毒OMP编码基因一样，tprL转录水平似乎受到位于基因启动子内的鸟苷(Gs)同聚序列长度的影响。这是一种称为相变的机制，通常涉及改变细菌病原体的表面抗原谱，以促进免疫逃避和/或适应宿主环境。
An effective syphilis vaccine should elicit antibodies to Treponema pallidum subsp. pallidum (T. p. pallidum) surface antigens to induce pathogen clearance through opsonophagocytosis. Although the combination of bioinformatics, structural, and functional analyses of T. p. pallidum genes to identify putative outer membrane proteins (OMPs) resulted in a list of potential vaccine candidates, still very little is known about whether and how transcription of these genes is regulated during infection. This knowledge gap is a limitation to vaccine design, as immunity generated to an antigen that can be down-regulated or even silenced at the transcriptional level without affecting virulence would not induce clearance of the pathogen, hence allowing disease progression. We report here that tp1031, the T. p. pallidum gene encoding the putative OMP and vaccine candidate TprL is differentially expressed in several T. p. pallidum strains, suggesting transcriptional regulation. Experimental identification of the tprL transcriptional start site revealed that a homopolymeric G sequence of varying length resides within the tprL promoter and that its length affects promoter activity compatible with phase variation. Conversely, in the closely related pathogen T. p. subsp. pertenue, the agent of yaws, where a naturally-occurring deletion has eliminated the tprL promoter region, elements necessary for protein synthesis, and part of the gene ORF, tprL transcription level are negligible compared to T. p. pallidum strains. Accordingly, the humoral response to TprL is absent in yaws-infected laboratory animals and patients compared to syphilis-infected subjects. The ability of T. p. pallidum to stochastically vary tprL expression should be considered in any vaccine development effort that includes this antigen. The role of phase variation in contributing to T. p. pallidum antigenic diversity should be further studied. Syphilis is still an endemic disease in many low- and middle-income countries and has been resurgent in high-income nations for almost two decades now. In endemic areas, syphilis still causes significant morbidity and mortality in patients, particularly when its causative agent, the bacterium Treponema pallidum subsp. pallidum is transmitted to the fetus during pregnancy. Although there are significant ongoing efforts to identify an effective syphilis vaccine to bring into clinical trials within the decade in the U.S., such efforts are partially hindered by the lack of knowledge on transcriptional regulation of many genes encoding vaccine candidates. Here, we start addressing this knowledge gap for the putative outer membrane protein (OMP) and vaccine candidates TprL, encoded by the tp1031 gene. As we previously reported for other putative OMP-encoding genes of the syphilis agent, tprL transcription level appears to be affected by the length of a homopolymeric sequence of guanosines (Gs) located within the gene promoter. This is a mechanism known as phase variation and often involved in altering the surface antigenic profile of a bacterial pathogen to facilitate immune evasion and/or adaptation to the host milieu.
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