Treponema pallidum genome sequencing from six continents reveals variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar.
Treponema pallidum genome sequencing from six continents reveals variability in vaccine candidate genes and dominance of Nichols clade strains in Madagascar.
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来自六大大洲的Treponema Pallidum基因组测序揭示了马达加斯加疫苗候选基因的变异性和尼科尔（Nichols）进化枝菌株的优势。
DOI：
10.1371/journal.pntd.0010063
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发表时间：
2021-12
影响因子：
3.8
通讯作者：
Greninger AL
中科院分区：
文献类型：
--
作者：
Lieberman NAP;Lin MJ;Xie H;Shrestha L;Nguyen T;Huang ML;Haynes AM;Romeis E;Wang QQ;Zhang RL;Kou CX;Ciccarese G;Dal Conte I;Cusini M;Drago F;Nakayama SI;Lee K;Ohnishi M;Konda KA;Vargas SK;Eguiluz M;Caceres CF;Klausner JD;Mitjà O;Rompalo A;Mulcahy F;Hook EW 3rd;Lukehart SA;Casto AM;Roychoudhury P;DiMaio F;Giacani L;Greninger AL
尽管梅毒螺旋体（T. pallidum）亚种对青霉素具有不变的敏感性。梅毒每年在全世界造成数百万梅毒病例，导致很高的发病率和死亡率，凸显了开发有效疫苗以遏制感染传播的紧迫性。一些技术挑战，包括直到最近还缺乏体外培养系统，阻碍了对全球收集的菌株多样性进行分类的努力。在这里，我们提供了 196 个梅毒螺旋体菌株（包括 191 个梅毒螺旋体亚种）的近乎完整的基因组。苍白球——直接对从 8 个国家和 6 大洲收集的患者样本进行测序。最大似然系统发育表明，大多数地点的样本主要是 SS14 分支。然而，99% (84/85) 的马达加斯加样本形成了五个不同的尼科尔斯分支中的两个。尽管重组在现代流行菌株的进化中并不常见，但我们发现了梅毒螺旋体亚种之间的多个假定的重组事件。苍白球和梅毒亚种。 endemicum，塑造了几个分支的基因组。时间分析将 Nichols 和 SS14 分支的最近共同祖先追溯到 1717 年（95% HPD：1543-1869），这与其他最近的研究一致。 SNP 积累率在各亚支之间存在显着差异，特别是在不同的 Nichols 亚支之间，并且在 Nichols A 亚支中与 TP0380（一种 ERCC3 样 DNA 修复解旋酶）中的 C394F 取代相关。我们的数据强调了编码假定的表面暴露外膜蛋白的基因变异在定义单独谱系中所发挥的作用，并为设计针对表面抗原的广泛保护性梅毒疫苗提供了关键资源。每年，由梅毒螺旋体（T. pallidum）亚种引起的性病和先天梅毒新病例数以百万计。梅毒螺旋体在全世界范围内被诊断出来，导致很高的发病率和死亡率。除了低收入国家梅毒流行之外，高收入国家的梅毒死灰复燃也凸显了对疫苗的需求。由于先前在生物体培养和测序方面的技术限制，梅毒螺旋体亚种现代菌株的遗传多样性程度。人们对梅毒仍知之甚少，这阻碍了广泛保护性疫苗的开发。在这项研究中，我们直接从六大洲八个国家的临床拭子中获得了 196 个接近完整的梅毒螺旋体基因组。其中，191 种被鉴定为梅毒螺旋体亚种。苍白球，包括 90 个尼科尔斯进化枝基因组。贝叶斯分析揭示了分支之间突变率的高度差异。有趣的是，突变率特别高的尼科尔斯分支在假定的 DNA 修复解旋酶中含有非同义突变。将测序数据与蛋白质结构预测相结合，我们在先前被确定为潜在疫苗候选者的几种蛋白质中发现了多种新的氨基酸变体。我们的数据有助于为当前开发具有广泛保护性的梅毒疫苗的努力提供信息。
In spite of its immutable susceptibility to penicillin, Treponema pallidum (T. pallidum) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T. pallidum strains–including 191 T. pallidum subsp. pallidum–sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T. pallidum subsp. pallidum and subsp. endemicum, shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543–1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens. Each year, millions of new cases of venereal and congenital syphilis, caused by the bacterium Treponema pallidum (T. pallidum) subsp. pallidum, are diagnosed worldwide, resulting in significant morbidity and mortality. Alongside endemic circulation of syphilis in low-income countries, disease resurgence in high-income nations has underscored the need for a vaccine. Due to prior technological limitations in culturing and sequencing the organism, the extent of the genetic diversity within modern strains of T. pallidum subsp. pallidum remains poorly understood, hampering development of a broadly protective vaccine. In this study, we obtained 196 near-complete T. pallidum genomes directly from clinical swabs from eight countries across six continents. Of these, 191 were identified as T. pallidum subsp. pallidum, including 90 Nichols clade genomes. Bayesian analysis revealed a high degree of variance in mutation rate among subclades. Interestingly, a Nichols subclade with a particularly high mutation rate harbors a non-synonymous mutation in a putative DNA repair helicase. Coupling sequencing data with protein structure prediction, we identified multiple novel amino acid variants in several proteins previously identified as potential vaccine candidates. Our data help inform current efforts to develop a broadly protective syphilis vaccine.
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影响因子：
3.1
作者：
Grimes M;Sahi SK;Godornes BC;Tantalo LC;Roberts N;Bostick D;Marra CM;Lukehart SA
通讯作者：
Lukehart SA
影响因子：
3.8
作者：
Djokic, Vitomir;Giacani, Lorenzo;Parveen, Nikhat
通讯作者：
Parveen, Nikhat
影响因子：
9.4
作者：
Brinkman, MB;McKevitt, M;Palzkill, T
通讯作者：
Palzkill, T
影响因子：
6.4
作者：
Cameron, CE;Lukehart, SA;Van Voorhis, WC
通讯作者：
Van Voorhis, WC
影响因子：
3.1
作者：
Giacani, Lorenzo;Brandt, Stephanie L.;Centurion-Lara, Arturo
通讯作者：
Centurion-Lara, Arturo