Synthetic within-cell flavivirus sensors

合成细胞内黄病毒传感器

基本信息

  • 批准号:
    BB/X002500/1
  • 负责人:
  • 金额:
    $ 83.78万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

The aim of the proposed study is to develop synthetic-biology sensors that can sit in living cells, essentially inert until the cell is infected by a virus, and then activate and respond. For this proposal, we focus on flaviviruses, a major group of viruses that includes mosquito-transmitted viruses dengue, Zika and yellow fever viruses, as well as some viruses transmitted by ticks, for example.When viruses infect a cell, they use a lot of the cell's own machinery for their replication, but they also have some proteins of their own, encoded in their own small genomes, that an uninfected cell does not have. These provide the basis for specific detection - the cell does not have these proteins and enzymes unless it is infected. Unlike the virus' sequence, which is very specific to individual virus types, or even strains of a single virus, these enzymatic activities are quite similar between different viruses of the same general group - e.g. flaviviruses, or mosquito-transmitted flaviviruses, so we expect to develop sensors that will respond to any of a range of viruses, perhaps to all mosquito-transmitted flaviviruses, rather than to just, for example Zika virus, or one strain of Zika virus.Such systems have several potential uses. One is in diagnostics. Sequence-based detection systems, such as PCR, need some prior knowledge of the virus sequence, and are very sensitive to variations in this sequence (i.e. may fail to detect a variant). More comprehensive approaches exist, such as complete sequencing, but these are currently relatively slow and expensive. Another standard approach involves applying the putative virus sample to cultured cells and looking for disruption of those cells (cytopathic effect, CPE), but this is a little slow, and not all viruses cause obvious pathology. We have developed prototype within-cell systems that appear to have superior characteristics, at least for some purposes. We will develop these and characterise them in detail, with project partners, to provide a set of tools complementary to current approaches.We will use the same approach in mosquitoes, to develop mosquitoes that respond in specific ways to infection by Zika virus and other flaviviruses. Our main aim here is for that response to reduce the ability of the mosquito to transmit the virus. Unlike humans, mosquitoes are not severely affected by these viruses, indeed it is important for the virus not to harm the mosquito much since it depends on her (always "her": only female mosquitoes bite) for transmission. If we can arrange that infected mosquitoes are unusually sensitive to infection, e.g. are killed by the virus, this will greatly reduce transmission. Such systems would additionally need to be spread into a target mosquito population in the wild. That is not part of this project, which is entirely lab-based, but potentially a future development if this project is successful.
这项研究的目的是开发合成生物传感器,这种传感器可以位于活细胞中,在细胞被病毒感染之前基本上是惰性的,然后激活并做出反应。对于这项提议,我们关注黄病毒,这是一组主要的病毒,包括蚊子传播的病毒登革热,寨卡病毒和黄热病病毒,以及一些由蜱传播的病毒,例如。当病毒感染细胞时,它们使用大量细胞自身的机器进行复制,但它们也有一些自己的蛋白质,编码在自己的小基因组中,这是未感染细胞所没有的。这些为特异性检测提供了基础-细胞没有这些蛋白质和酶,除非它被感染。与病毒的序列不同,病毒的序列对单个病毒类型或甚至单一病毒的菌株都非常特异,这些酶活性在同一大类的不同病毒之间非常相似-例如黄病毒或蚊子传播的黄病毒,因此我们希望开发出能够对一系列病毒中的任何一种做出反应的传感器,也许是对所有蚊子传播的黄病毒,而不仅仅是,例如寨卡病毒或寨卡病毒的一种毒株。一个是诊断。基于序列的检测系统,如PCR,需要一些病毒序列的先验知识,并且对该序列的变异非常敏感(即可能无法检测到变体)。存在更全面的方法,例如完全测序,但这些方法目前相对缓慢且昂贵。另一种标准方法涉及将推定的病毒样品应用于培养的细胞并寻找这些细胞的破坏(细胞病变效应,CPE),但这有点慢,并且并非所有病毒都会引起明显的病理。我们已经开发出了细胞内系统的原型,至少在某些方面具有上级特性。我们将与项目合作伙伴一起开发这些工具,并对其进行详细的分析,以提供一套补充现有方法的工具。我们将在蚊子中使用相同的方法,以开发以特定方式对寨卡病毒和其他黄病毒感染做出反应的蚊子。我们的主要目标是通过这种反应来降低蚊子传播病毒的能力。与人类不同的是,蚊子不会受到这些病毒的严重影响,事实上,病毒对蚊子的伤害不太大是很重要的,因为它依赖于她(总是“她”:只有雌性蚊子叮咬)进行传播。如果我们能够安排受感染的蚊子对感染异常敏感,例如被病毒杀死,这将大大减少传播。这种系统还需要传播到野外的目标蚊子种群中。这不是这个完全基于实验室的项目的一部分,但如果这个项目成功的话,这可能是未来的发展。

项目成果

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Luke Alphey其他文献

Culex quinquefasciatus: status as a threat to island avifauna and options for genetic control
  • DOI:
    10.1186/s43170-021-00030-1
  • 发表时间:
    2021-03-04
  • 期刊:
  • 影响因子:
    2.700
  • 作者:
    Tim Harvey-Samuel;Thomas Ant;Jolene Sutton;Chris N. Niebuhr;Samoa Asigau;Patricia Parker;Steven Sinkins;Luke Alphey
  • 通讯作者:
    Luke Alphey
Can CRISPR-Cas9 gene drives curb malaria?
CRISPR-Cas9 基因驱动能遏制疟疾吗?
  • DOI:
    10.1038/nbt.3473
  • 发表时间:
    2016-02-05
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    Luke Alphey
  • 通讯作者:
    Luke Alphey
Transgenic expression of cif genes from Wolbachia strain wAlbB recapitulates cytoplasmic incompatibility in Aedes aegypti
沃尔巴克氏菌 wAlbB 菌株 cif 基因的转基因表达再现了埃及伊蚊的细胞质不相容性
  • DOI:
    10.1101/2023.09.01.555917
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Cameron J McNamara;T. Ant;T. Harvey‐Samuel;Helen White;Julien Martinez;Luke Alphey;S. Sinkins
  • 通讯作者:
    S. Sinkins
Challenges in developing a split drive targeting dsx for the genetic control of the invasive malaria vector Anopheles stephensi
  • DOI:
    10.1186/s13071-025-06688-0
  • 发表时间:
    2025-02-07
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Mireia Larrosa-Godall;Joshua X. D. Ang;Philip T. Leftwich;Estela Gonzalez;Lewis Shackleford;Katherine Nevard;Rob Noad;Michelle A. E. Anderson;Luke Alphey
  • 通讯作者:
    Luke Alphey
Optimization of SgRNA expression with RNA pol III regulatory elements in Anopheles stephensi
斯蒂芬按蚊中利用 RNA pol III 调控元件优化 sgRNA 表达
  • DOI:
    10.1038/s41598-025-98557-0
  • 发表时间:
    2025-04-18
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Estela Gonzalez;Michelle A. E. Anderson;Joshua X. D. Ang;Katherine Nevard;Lewis Shackleford;Mireia Larrosa-Godall;Philip T. Leftwich;Luke Alphey
  • 通讯作者:
    Luke Alphey

Luke Alphey的其他文献

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{{ truncateString('Luke Alphey', 18)}}的其他基金

Engineering insects for novel food/feed and waste management
用于新型食品/饲料和废物管理的工程昆虫
  • 批准号:
    BB/Y008014/1
  • 财政年份:
    2024
  • 资助金额:
    $ 83.78万
  • 项目类别:
    Research Grant
SuperSIT - Sustainable Sterile Insect Technique
SuperSIT - 可持续昆虫不育技术
  • 批准号:
    EP/X025535/1
  • 财政年份:
    2023
  • 资助金额:
    $ 83.78万
  • 项目类别:
    Research Grant
Genetic approaches to reducing vector competence of Aedes aegypti for chikungunya virus
降低埃及伊蚊对基孔肯雅病毒载体能力的遗传方法
  • 批准号:
    MC_PC_16028
  • 财政年份:
    2016
  • 资助金额:
    $ 83.78万
  • 项目类别:
    Intramural

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