Exploring the coevolutionary potential of chikungunya virus and its Aedes mosquito vectors

探索基孔肯雅病毒及其伊蚊媒介的共同进化潜力

基本信息

批准号：
10711906
负责人：
Elizabeth Ann McGraw
金额：
$ 69.15万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-19 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711906
关键词：
Aedes Affect African Americas Arboviruses Area Arthritis Asian CRISPR/Cas technology Candidate Disease Gene Caribbean region Cells Chikungunya virus Chronic Cost of Illness Country Culicidae Dengue Virus Development Disease Disease Outbreaks Distant E protein Epidemiology Evolution Family Future Gene Proteins General Practitioners Genes Genetic Genetic Variation Genomics Heritability Immune response In Vitro Indian Ocean Individual Infection Island Knowledge Latin America Link Maps Measures Mediating Methods Modification Morbidity - disease rate Mutagenesis Mutation Outcome Pathway interactions Pharmacotherapy Phenotype Population Predisposition Public Health RNA Interference Refractory Reporter Reporting Resistance Risk Role Salivary Glands Shapes Site-Directed Mutagenesis South African System Techniques Testing Time Tissues Vaccines Variant Viral Viral Genome Viral Vector Virus Work candidate identification chikungunya chikungunya infection env Gene Products experience fitness genetic approach genetic architecture genetic resistance genetic variant genome sequencing genome wide association study improved invention novel stem tool transmission process vector vector competence vector control vector mosquito vector-borne viral resistance viral transmission

项目摘要

SUMMARY Chikungunya virus (CHIKV) has become a global problem since it spread from the Indian Ocean region, around the globe. In 2014, this expansion included a major outbreak in Latin America and the Caribbean that has led to endemicity in several countries. The cost of the disease as a public health issue is substantial, given the chronic arthritis that tends to arise post-infection. Without a vaccine or drug treatment, vector control is the only solution for limiting the disease. CHIKV is transmitted by two species of mosquito, Aedes albopictus and Aedes aegypti, which have spread to inhabit much of the temperate and tropical regions of the world. Because it is very distantly related to its more ubiquitous cousin, dengue virus (DENV), mosquito populations have had little opportunity to evolve resistance to CHIKV. Since both DENV and CHIKV cause fitness reductions in mosquitoes, they have the potential to act as a selective force in populations where they occur. CHIKV’s potential for expanded impact is concerning, given that it appears better able to infect mosquitoes than DENV. In Aim 1, we take an experimental evolution approach to understand the relative potential for mosquitoes to evolve resistance to CHIKV compared to DENV. In the evolved lines we will use genome-wide association to identify candidate SNPs/genes that underpin virus resistance. Using efficient CRISPR-Cas9 methods developed specifically for Ae. aegypti, we can then test the functional involvement of top candidate genes in resistance. In Aim 2, we explore the functional importance of the suite of genetic variants that exist globally in a CHIKV envelope protein-encoding gene (E2). E2 mediates entry into mosquito tissues, and variation in the gene can affect vector transmissibility. In completing these aims, we will generate new tools and apply emerging tools in a new context including the use of improved fluorescent reporter viruses in mosquitoes rather than in vitro and the adaptation of the ‘Vectorchip’ vector competence system for use with CHIKV and Ae. albopictus. The key knowledge gaps we will address are (i) whether with the assistance of mosquito genetic diversity and resistance evolution if CHIKV transmission is likely to evolve to lower levels with time, (ii) a list of potential anti-CHIKV and shared anti- CHIKV and DENV mosquito genes to target in genetic modification approaches, and (iii) an understanding of how circulating E2 variants in CHIKV genome may shape mosquito infectivity and the global landscape of CHIKV epidemiology.

概括基孔肯雅病毒（CHIKV）自印度洋地区传播以来已成为全球性问题， 2014年，这种扩张包括在拉丁美洲和加勒比地区的大规模爆发。这导致该疾病在一些国家流行，作为一个公共卫生问题，其代价是巨大的，鉴于慢性关节炎在没有疫苗或药物治疗的情况下会出现感染后的倾向。控制是限制该疾病的唯一解决方案 CHIKV 由两种蚊子（伊蚊）传播。白纹伊蚊和埃及伊蚊已蔓延至大部分温带和热带地区因为它与其更普遍的表亲——登革热病毒（DENV）——蚊子有很远的亲缘关系。由于 DENV 和 CHIKV 均引起，因此人群几乎没有机会进化出对 CHIKV 的抵抗力。蚊子的适应度降低，它们有可能在蚊子种群中充当选择性力量鉴于 CHIKV 的感染能力似乎更强，其扩大影响的潜力令人担忧。在目标 1 中，我们采用实验进化方法来了解相关性。与 DENV 相比，蚊子进化出对 CHIKV 的抵抗力的潜力。全基因组关联，以识别支持病毒抗性的候选 SNP/基因。专门针对埃及伊蚊开发的 CRISPR-Cas9 方法，然后我们可以测试其功能参与情况。在目标 2 中，我们探讨了这组遗传基因的功能重要性。 CHIKV 包膜蛋白编码基因 (E2) 中普遍存在的变体介导进入。蚊子组织和基因变异会影响载体的传播能力。将产生新工具并在新环境中应用新兴工具，包括使用改进的蚊子体内而不是体外的荧光报告病毒以及“Vectorchip”载体的适应我们将解决 CHIKV 和白纹伊蚊的能力系统。 (i) 是否借助蚊子遗传多样性和抗性进化的帮助，如果 CHIKV 随着时间的推移，传播可能会降低到较低水平，(ii) 潜在抗 CHIKV 和共享抗病毒列表基因改造方法中针对的 CHIKV 和 DENV 蚊子基因，以及 (iii) 了解 CHIKV 基因组中循环的 E2 变体如何影响蚊子的传染性和全球格局 CHIKV 流行病学。