Dissecting cell surface protein diversity to enhance leptospiral vaccine efficacy.

剖析细胞表面蛋白质多样性以增强钩端螺旋体疫苗的功效。

基本信息

  • 批准号:
    BB/W016133/1
  • 负责人:
  • 金额:
    $ 93.91万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

Leptospirosis, caused by Leptospira bacteria, is a worldwide, severe infectious disease affecting several different host species including cattle, dogs and man. Globally, cattle are greatly afflicted resulting in severe economic losses, reduced food security, substantial antimicrobial use and animal to man (zoonotic) transmission. Economic cost to the UK is £22.3 million/year with much greater costs expected for tropical regions, including many low to middle income countries (LMICs), due to substantially greater disease burden and more severe disease. Current bovine leptospirosis (BL) vaccines have a limited range of specificity and require cold chain transport and storage, which is problematic in the many tropical, frequently LMIC regions with greatest disease burden. Making vaccines more broadly protective and easily accessible will increase uptake globally, decreasing global antibiotic use and antimicrobial resistance development. This is especially important for leptospirosis which is considered to be emerging/re-emerging globally and being driven by global warming and associated increases in extreme climatic events, such as flooding. Bacterial surface proteins are considered important targets to provide cross-protective and long lasting immunity against a range of Leptospira species and serovars. Immune evasion by leptospires, is considered to involve these bacteria coating themselves with host molecules. Whilst the different leptospire bacteria involved in disease are diverse, they must have near identical machinery for this immune evasion which must be present on the bacterial surface to allow for host binding and/or damage and therefore represent ideal vaccine targets. Thus, characterisation of key bacterial surface proteins, especially those involved in immune evasion and determining their mechanism of interaction should allow for development of novel vaccines or therapeutics. Recent research, mutating bacterial surface proteins to prevent binding of host molecules, as well as enhancing protein stability, has increased the protective ability of these bacterial components when used as vaccines. The application of such novel protein engineering has been used in the development pathway for an important human pathogen vaccine which is now licensed and can now be applied to veterinary pathogens. Here, we combine synthetic biology, artificial intelligence and in silico (bioinformatic) approaches to guide engineering of key cell surface proteins to develop a novel thermostable vaccine with broad Leptospira specificity and enhanced efficacy.This study will 1) investigate vaccine candidate diversity across leptospire species including surveying whether variants from some species exhibit adhesion preference for molecules from specific host species resulting in known host specificity and identify, whether variants from commensal (harmless) relatives lack ability to attach to host molecules, 2) use sequence diversity/conservation and differences in adhesion ability together with artificial intelligence (AI) generated structural models with in silico approaches to engineer the surface proteins to restrict host interaction which in line with recent human pathogen disease work should allow for more effective vaccines, 3) use sequence diversity together with AI generated structural models and in silico approaches to synthesise surface proteins with enhanced stability, 4) use a rodent models of disease to identify those engineered bacterial surface proteins most likely to offer protection from a range of the disease causing bacteria.Investigating BL vaccine candidates by the diverse and comprehensive methods described above, should help characterise the causal bacteria, improve understanding of the disease, substantially progress the vaccine development pipeline and/or identify novel therapeutics. Such studies are both timely and much needed to enable the prevention or even eradication of this severe, important global disease.
钩端螺旋体病是由钩端螺旋体属细菌引起的一种世界性的严重传染病,影响包括牛、狗和人在内的几种不同的宿主物种。在全球范围内,牛受到极大的折磨,导致严重的经济损失、粮食安全降低、大量使用抗菌剂和动物到人(人畜共患)传播。英国的经济成本为2230万英镑/年,热带地区的成本预计会更高,包括许多低收入到中等收入国家(LMIC),因为疾病负担更大,疾病更严重。目前的牛钩端螺旋体病(BL)疫苗具有有限的特异性范围,需要冷链运输和储存,这在许多热带地区,通常是LMIC地区的疾病负担最大的问题。使疫苗具有更广泛的保护性和更容易获得将增加全球的吸收,减少全球抗生素的使用和抗菌素耐药性的发展。这对于钩端螺旋体病尤其重要,因为钩端螺旋体病被认为是全球新出现/重新出现的疾病,并受到全球变暖和极端气候事件(如洪水)相关增加的驱动。细菌表面蛋白被认为是提供针对一系列钩端螺旋体物种和血清型的交叉保护和持久免疫的重要靶标。钩端螺旋体的免疫逃避被认为涉及这些细菌用宿主分子包裹自己。虽然疾病中涉及的不同钩端螺旋体细菌是多样的,但它们必须具有几乎相同的用于这种免疫逃避的机制,该机制必须存在于细菌表面上以允许宿主结合和/或损伤,因此代表理想的疫苗靶标。因此,表征关键的细菌表面蛋白,特别是那些参与免疫逃避和确定它们的相互作用机制,应允许开发新的疫苗或治疗剂。最近的研究,突变细菌表面蛋白以防止宿主分子结合,以及增强蛋白质稳定性,增加了这些细菌成分用作疫苗时的保护能力。这种新型蛋白质工程的应用已被用于重要的人类病原体疫苗的开发途径中,该疫苗现已获得许可,现在可以应用于兽医病原体。在这里,我们结合了联合收割机合成生物学,人工智能和计算机(生物信息学)方法来指导关键细胞表面蛋白的工程化,以开发具有广泛钩端螺旋体特异性和增强功效的新型热稳定疫苗。研究钩端螺旋体物种间的候选疫苗多样性,包括调查来自某些物种的变体是否表现出对来自特定宿主物种的分子的粘附偏好,宿主特异性和识别,是否从寄生虫变异(无害的)亲属缺乏附着到宿主分子的能力,2)使用序列多样性/保守性和粘附能力的差异以及人工智能(AI)生成的结构模型,用计算机模拟方法来工程化表面蛋白以限制宿主相互作用,这与最近的人类病原体疾病工作一致,应该允许更有效的疫苗,3)使用序列多样性以及AI生成的结构模型和计算机模拟方法来合成具有增强的稳定性的表面蛋白,4)使用啮齿动物疾病模型来鉴定那些最有可能提供对一系列致病细菌的保护的工程化细菌表面蛋白。通过上述多样化和全面的方法研究BL疫苗候选物,应该有助于鉴定致病细菌,提高对疾病的理解,大大推进疫苗开发管道和/或确定新的治疗方法。这些研究是及时的,也是非常必要的,以便能够预防甚至根除这一严重的全球性疾病。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Characterisation of Putative Outer Membrane Proteins from Leptospira borgpetersenii Serovar Hardjo-Bovis Identifies Novel Adhesins and Diversity in Adhesion across Genomospecies Orthologs
  • DOI:
    10.3390/microorganisms12020245
  • 发表时间:
    2024-02-01
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Kamaruzaman,Intan Noor Aina;Staton,Gareth James;Evans,Nicholas James
  • 通讯作者:
    Evans,Nicholas James
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Nicholas Evans其他文献

Mundari reciprocals, In Nicholas Evans, Alice Gaby, Stephen Levinson and Asifa Majid (ed.) Reciprocals and Semantic Typology
Mundari 倒数,Nicholas Evans、Alice Gaby、Stephen Levinson 和 Asifa Majid(编辑)《倒数和语义类型学》
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nicholas Evans;Toshiki Osada
  • 通讯作者:
    Toshiki Osada
The Dictionary of Mundari Expressives
蒙达里表达辞典
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nathan Badenoch;Toshiki Osada;Madhu Purti;Nicholas Evans;Masato Kobayashi;Masayuki Onishi;Durga Pada Datta
  • 通讯作者:
    Durga Pada Datta
How universal is complementation? And does corpus type influence our answer?
互补性有多普遍?
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nicholas Evans;Wayan Arka;Danielle Barth;Henrik Bergqvist;Christian Doehler;Sonja Gipper;Dolgor Guntsetseg;Yukinori Kimoto;Dominique Knuchel;Hitomi Ono;Eka Pratiwi;Saskia van Putten;Alan Rumsey;Andrea Schalley;Stefan Schnell;Asako Shiohara,
  • 通讯作者:
    Asako Shiohara,
t-DCF: a detection cost function for the tndem assessment of spoofing countermeasures and automatic speaker verification
t-DCF:用于欺骗对策和自动说话人验证的 TNDEM 评估的检测成本函数
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Tomi Kinnunen;Kong Aik Lee;Hector Delgado;Nicholas Evans;Massimiliano Todisco;Md Sahidullah;Junichi Yamagishi;and Douglas A. Reynolds
  • 通讯作者:
    and Douglas A. Reynolds
IYSC10. Review of Serious Complications from Embolosclerotherapy of Head and Neck Vascular Malformations in a Single Specialist Center
  • DOI:
    10.1016/j.jvs.2019.04.044
  • 发表时间:
    2019-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Helena Smith;Chung Sim Lim;Nicholas Evans;Anthie Papadopoulou;Mohamed Khalifa;Janice Tsui;George Hamilton;Jocelyn A. Brookes
  • 通讯作者:
    Jocelyn A. Brookes

Nicholas Evans的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Nicholas Evans', 18)}}的其他基金

Dissecting treponemal immune-modulation to enable disease control.
剖析密螺旋体免疫调节以实现疾病控制。
  • 批准号:
    BB/X016226/1
  • 财政年份:
    2024
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant
MICA: Ultrasound-responsive agents for non-invasive fracture healing
MICA:用于无创骨折愈合的超声响应剂
  • 批准号:
    MR/X009793/1
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant
New Frontiers in Particle Physics, Cosmology and Gravity
粒子物理学、宇宙学和引力的新领域
  • 批准号:
    ST/T000775/1
  • 财政年份:
    2020
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant
Bubbles to Bond Broken Bones: targeted drug delivery for fracture repair
气泡粘合断骨:用于骨折修复的靶向药物输送
  • 批准号:
    EP/R013594/1
  • 财政年份:
    2018
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant
Standard Grant: Ethical Algorithms in Autonomous Vehicles
标准拨款:自动驾驶汽车中的道德算法
  • 批准号:
    1734521
  • 财政年份:
    2017
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Standard Grant
Unravelling the aetiology of contagious ovine digital dermatitis.
揭示传染性羊指皮炎的病因。
  • 批准号:
    BB/N002121/1
  • 财政年份:
    2016
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant
Dissecting the molecular diversity of bovine digital dermatitis treponemes.
剖析牛指皮炎密螺旋体的分子多样性。
  • 批准号:
    BB/K009443/1
  • 财政年份:
    2013
  • 资助金额:
    $ 93.91万
  • 项目类别:
    Research Grant

相似国自然基金

全细胞疫苗Cell@MnO2的乳腺癌术后免疫响应监测与放射免疫治疗研究
  • 批准号:
    QN25H220002
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
染色体外环状DNA以cell-in-cell途径促进基因横向传递和扩增的研究
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    15.0 万元
  • 项目类别:
    省市级项目
GMFG/F-actin/cell adhesion 轴驱动 EHT 在造 血干细胞生成中的作用及机制研究
  • 批准号:
    TGY24H080011
  • 批准年份:
    2024
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
基于In-cell NMR策略对“舟楫之剂”桔梗中引经药效物质的快速发现研究
  • 批准号:
    82305053
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
骨髓ISG+NAMPT+中性粒细胞介导抗磷脂综合征B细胞异常活化的机制研究
  • 批准号:
    82371799
  • 批准年份:
    2023
  • 资助金额:
    47.00 万元
  • 项目类别:
    面上项目
配子生成素GGN不同位点突变损伤分子伴侣BIP及HSP90B1功能导致精子形成障碍的发病机理
  • 批准号:
    82371616
  • 批准年份:
    2023
  • 资助金额:
    49.00 万元
  • 项目类别:
    面上项目
糖尿病ED中成纤维细胞衰老调控内皮细胞线粒体稳态失衡的机制研究
  • 批准号:
    82371634
  • 批准年份:
    2023
  • 资助金额:
    49.00 万元
  • 项目类别:
    面上项目
利用CRISPR内源性激活Atoh1转录促进前庭毛细胞再生和功能重建
  • 批准号:
    82371145
  • 批准年份:
    2023
  • 资助金额:
    46.00 万元
  • 项目类别:
    面上项目
IL-4协同精氨酸优化种植初期巨噬细胞胞葬作用和成骨微环境的作用及机制研究
  • 批准号:
    82370923
  • 批准年份:
    2023
  • 资助金额:
    48.00 万元
  • 项目类别:
    面上项目
胆固醇合成蛋白CYP51介导线粒体通透性转换诱发Th17/Treg细胞稳态失衡在舍格伦综合征中的作用机制研究
  • 批准号:
    82370976
  • 批准年份:
    2023
  • 资助金额:
    48.00 万元
  • 项目类别:
    面上项目

相似海外基金

Dissecting the role of IER3IP1 in neurogenesis and brain malformation
剖析 IER3IP1 在神经发生和脑畸形中的作用
  • 批准号:
    10672753
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the Differential Impacts of Toll-like Receptor 9 Agonism on the Capacity of Human Natural Killer Cells to Mediate Target Cell Killing
剖析 Toll 样受体 9 激动剂对人类自然杀伤细胞介导靶细胞杀伤能力的不同影响
  • 批准号:
    10730451
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
Nanobodies for Dissecting the Structure and Function of Oligomeric BAX
用于剖析寡聚 BAX 结构和功能的纳米抗体
  • 批准号:
    10677287
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the peptide motifs controlling coronavirus infections
剖析控制冠状病毒感染的肽基序
  • 批准号:
    10648391
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the Intracellular and Extracellular Role of TREM2 in the Pathogenesis of Non-Alcoholic Steatohepatitis.
剖析 TREM2 在非酒精性脂肪性肝炎发病机制中的细胞内和细胞外作用。
  • 批准号:
    10720352
  • 财政年份:
    2023
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the roles and molecular mechanisms of Wnt signal transduction at the Drosophila neuromuscular junction
剖析果蝇神经肌肉接头Wnt信号转导的作用和分子机制
  • 批准号:
    10527669
  • 财政年份:
    2022
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the Diverse Roles of Importin α at the Plasma Membrane
剖析输入α在质膜上的不同作用
  • 批准号:
    10673789
  • 财政年份:
    2022
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the Molecular Mechanisms that Govern Notch Mediated Skeletal Stem Cell Maintenance Throughout Adulthood/Aging.
剖析控制 Notch 介导的整个成年/衰老过程中骨骼干细胞维持的分子机制。
  • 批准号:
    10387942
  • 财政年份:
    2022
  • 资助金额:
    $ 93.91万
  • 项目类别:
Aptamer tools for dissecting HIV-1 capsid function and identifying accessible, biologically relevant interaction surfaces.
用于剖析 HIV-1 衣壳功能并识别可访问的、生物学相关的相互作用表面的适体工具。
  • 批准号:
    10655852
  • 财政年份:
    2022
  • 资助金额:
    $ 93.91万
  • 项目类别:
Dissecting the mechanisms by which chromosomal instability impacts anti-Disialoganglioside responses in neuroblastoma
剖析染色体不稳定性影响神经母细胞瘤抗双唾液酸神经节苷脂反应的机制
  • 批准号:
    10654574
  • 财政年份:
    2022
  • 资助金额:
    $ 93.91万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了