Mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito Aedes aegypti.
Mimicking superinfection exclusion disrupts alphavirus infection and transmission in the yellow fever mosquito Aedes aegypti.
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DOI：
10.1073/pnas.2303080120
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发表时间：
2023-09-12
影响因子：
11.1
通讯作者：
Alphey, Luke
中科院分区：
文献类型：
--
作者：
Reitmayer, Christine M.;Levitt, Emily;Basu, Sanjay;Atkinson, Barry;Fragkoudis, Rennos;Merits, Andres;Lumley, Sarah;Larner, Will;Diaz, Adriana V.;Rooney, Sara;Thomas, Callum J. E.;von Wyschetzki, Katharina;Rausalu, Kai;Alphey, Luke
虫媒病毒是全世界人类健康的重大负担。由于缺乏获得许可的疫苗和抗病毒治疗药物，目前的疾病预防主要集中在通过杀虫剂进行病媒控制。基因控制技术有潜力提供更可持续的蚊媒控制手段。我们研究了一种与病毒株无关、低耐药性的合成生物学方法，具有广谱潜力，可以控制基孔肯雅病毒等甲病毒的传播。我们方法的独特性是基于利用这些病毒自身的机制来防止同一细胞被多种不同的甲病毒感染——这种现象称为重复感染排除。表现出这种机制的转基因蚊子种群可能会减少相关地区的疾病传播。多种病毒，包括病原病毒、噬菌体，甚至植物病毒，会引起一种称为重复感染排除的现象，即当前感染的细胞对相同或密切相关的病毒的二次感染具有抵抗力。在甲病毒中，这一过程被认为至少部分是由病毒蛋白酶（nsP2）介导的，该酶负责将非结构多蛋白（P123和P1234）加工成单个蛋白（nsP1-nsP4），形成病毒复制复合物。采用合成生物学方法，我们通过在埃及伊蚊中产生类似重复感染排除的状态来模仿这种自然发生的现象，使它们对甲病毒感染具有抵抗力。通过在蚊子细胞和转基因蚊子中人工表达辛德比斯病毒（SINV）和基孔肯雅病毒（CHIKV）nsP2，我们证明了病毒感染后细胞中SINV和CHIKV病毒复制率的降低，以及蚊子中感染率、病毒滴度和传播潜力的降低。
Arboviruses are a significant burden to human health worldwide. Due to the lack of licensed vaccines and antiviral therapeutics, current disease prevention mainly focuses on vector control by means of insecticides. Genetic control technologies have the potential to provide more sustainable means of mosquito vector control. We have investigated a virus-strain independent, low-resistance, synthetic biology approach with broad spectrum potential to control the transmission of alphaviruses such as chikungunya virus. The uniqueness of our approach is based on utilizing a mechanism these viruses use themselves to prevent infection of the same cell with multiple different alphaviruses—a phenomenon termed superinfection exclusion. A population of genetically modified mosquitoes exhibiting this mechanism could result in reduced disease transmission in a relevant area. Multiple viruses, including pathogenic viruses, bacteriophages, and even plant viruses, cause a phenomenon termed superinfection exclusion whereby a currently infected cell is resistant to secondary infection by the same or a closely related virus. In alphaviruses, this process is thought to be mediated, at least in part, by the viral protease (nsP2) which is responsible for processing the nonstructural polyproteins (P123 and P1234) into individual proteins (nsP1–nsP4), forming the viral replication complex. Taking a synthetic biology approach, we mimicked this naturally occurring phenomenon by generating a superinfection exclusion-like state in Aedes aegypti mosquitoes, rendering them refractory to alphavirus infection. By artificially expressing Sindbis virus (SINV) and chikungunya virus (CHIKV) nsP2 in mosquito cells and transgenic mosquitoes, we demonstrated a reduction in both SINV and CHIKV viral replication rates in cells following viral infection as well as reduced infection prevalence, viral titers, and transmission potential in mosquitoes.
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影响因子：
3.7
作者：
Strauss EG;De Groot RJ;Levinson R;Strauss JH
通讯作者：
Strauss JH
影响因子：
4.6
作者：
Liu WL;Hsu CW;Chan SP;Yen PS;Su MP;Li JC;Li HH;Cheng L;Tang CK;Ko SH;Tsai HK;Tsai ZT;Akbari OS;Failloux AB;Chen CH
通讯作者：
Chen CH
蚊子细胞中α非结构性蛋白2（NSP2）的表达抑制病毒RNA的复制，以蛋白酶的活性依赖性和非依赖性方式抑制。
DOI：
10.3390/v14061327
发表时间：
2022-06-17
期刊：
Viruses
影响因子：
--
作者：
通讯作者：
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DOI：
10.1073/pnas.1000251107
发表时间：
2010-03-09
影响因子：
11.1
作者：
Fu, Guoliang;Lees, Rosemary S.;Alphey, Luke
通讯作者：
Alphey, Luke
DOI：
10.1073/pnas.97.22.11984
发表时间：
2000-10-24
影响因子：
11.1
作者：
Baird, GS;Zacharias, DA;Tsien, RY
通讯作者：
Tsien, RY