The L-DBF vaccine cross protects mice against different Shigella serotypes after prior exposure to the pathogen.
The L-DBF vaccine cross protects mice against different Shigella serotypes after prior exposure to the pathogen.
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DOI：
10.1128/spectrum.00062-23
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发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
Picking, Wendy L.
中科院分区：
文献类型：
--
作者：
Lu, Ti;Howlader, Debaki R.;Das, Sayan;Dietz, Zackary K.;Nagel, Aaron C.;Whittier, Sean K.;Picking, William D.;Picking, Wendy L.
志贺氏菌病（细菌性痢疾）是一种由志贺氏菌属成员引起的严重腹泻病，全世界每年产生 9000 万例病例。志贺氏菌 III 型分泌系统 (T3SS) 是一种特殊的分泌系统，是其用来感染结肠粘膜的主要毒力因子。 III 型分泌装置 (T3SA) 蛋白 IpaB 和 IpaD 以及基因融合蛋白 DBF 已被证明可以保护小鼠免受志贺氏菌感染。致命肺部模型中的感染。在之前的一项研究中，我们将产肠毒素大肠杆菌的致死毒素活性部分 LTA1 与 DBF 融合，产生了一种自我佐剂候选疫苗 L-DBF，它可以交叉保护小鼠免受福氏志贺氏菌和宋内氏志贺氏菌四种血清型的侵害。在这里，我们让小鼠接触一到两剂亚致死剂量的福氏志贺菌 2a，以确定 L-DBF 在宿主中诱导的免疫反应是否会受到同源或异源志贺氏菌血清型先前感染的影响。我们证明，预感染两剂亚致死剂量的福氏链球菌 2a 不会引起针对宋内链球菌的交叉保护，而接种 L-DBF 则会产生交叉保护。我们的结果表明，L-DBF 是一种可行的候选疫苗，即使在之前接触过志贺氏菌后也能提供针对不同血清型的交叉保护。这项工作提供了一个概念证明，即新型亚单位疫苗不仅可以保护幼稚宿主免受志贺氏菌攻击，而且还可以在先前感染相同或不同志贺氏菌血清型后免受攻击。志贺氏菌病是世界低收入和中等收入地区的地方病，儿童尤其容易受到感染。在许多情况下，当地人群中已经存在抗体，在开发和测试针对志贺氏菌感染的疫苗时应考虑先前接触的影响。我们的研究表明，L-DBF 诱导的免疫反应不会因之前接触过这种病原体而受到不利影响。此外，在未接触志贺氏菌的已接种疫苗的小鼠的肺部观察到有些不同的细胞因子谱，这表明志贺氏菌感染和 L-DBF 疫苗接种引起的免疫反应遵循不同的途径。
Shigellosis (bacillary dysentery) is a severe diarrheal disease caused by members of the genus Shigella, which results in 90 million cases annually around the world. The Shigella type III secretion system (T3SS) is a specialized secretion system that is the primary virulence factor it uses to infect the colonic mucosa. The type III secretion apparatus (T3SA) proteins IpaB and IpaD, as well as the genetic fusion, DBF, have been demonstrated to protect mice from Shigella spp. infection in a lethal pulmonary model. In a previous study, we fused LTA1, the active moiety of lethal toxin from enterotoxigenic Escherichia coli to DBF to produce a self-adjuvanting vaccine candidate L-DBF, which cross-protected mice against four serotypes of Shigella flexneri and Shigella sonnei. Here, we exposed mice with one or two sublethal doses of S. flexneri 2a to identify whether the immune response induced by L-DBF in the host would be affected by prior infection by homologous or heterologous Shigella serotypes. We demonstrate that pre-infection with two sublethal doses of S. flexneri 2a did not elicit cross-protection against S. sonnei, while vaccination with L-DBF did. Our results indicate that L-DBF is a feasible vaccine candidate that offers cross-protection against Shigella’s different serotypes even after prior exposure to the pathogen. This work provides a proof of concept that a novel subunit vaccine can not only protect a naïve host from Shigella challenge, but also can protect against challenge after prior infection by the same or different Shigella serotypes. Shigellosis is endemic to low- and middle-income regions of the world where children are especially vulnerable. In many cases, there are pre-existing antibodies in the local population and the effect of prior exposure should be considered in the development and testing of vaccines against Shigella infection. Our study shows that L-DBF-induced immune responses are not adversely affected by prior exposure to this pathogen. Moreover, somewhat different cytokine profiles were observed in the lungs of vaccinated mice not having been exposed to Shigella, suggesting that the immune responses elicited by Shigella infection and L-DBF vaccination follow different pathways.
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影响因子：
16.6
作者：
Hawkey J;Paranagama K;Baker KS;Bengtsson RJ;Weill FX;Thomson NR;Baker S;Cerdeira L;Iqbal Z;Hunt M;Ingle DJ;Dallman TJ;Jenkins C;Williamson DA;Holt KE
通讯作者：
Holt KE
DOI：
10.1073/pnas.1300981110
发表时间：
2013-03-19
影响因子：
11.1
作者：
Salgado-Pabon, Wilmara;Celli, Susanna;Phalipon, Armelle
通讯作者：
Phalipon, Armelle
影响因子：
3.9
作者：
Rew V;Mook P;Trienekens S;Baker KS;Dallman TJ;Jenkins C;Crook PD;Thomson NR
通讯作者：
Thomson NR
影响因子：
14.2
作者：
Allen, H.;Mitchell, H. D.;Jenkins, C.
通讯作者：
Jenkins, C.
影响因子：
3.1
作者：
Olive, Andrew J.;Kenjale, Roma;Picking, William D.
通讯作者：
Picking, William D.