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

• 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
• 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

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 自从印度洋地区传播以来 全球。 2014年，这一扩展包括拉丁美洲和加勒比海地区的一次大爆发 这导致了几个国家的内在性。该疾病作为公共卫生问题的成本很大， 鉴于感染后倾向于出现的慢性关节炎。没有疫苗或药物治疗，载体 控制是限制疾病的唯一解决方案。 Chikv由两种蚊子埃德斯传播 白化病和埃及埃及埃及，它们已经扩散到居住在许多温度和热带地区 世界。因为它与更加普遍的表弟登革热病毒（DENV），蚊子非常遥远 人口几乎没有机会发展对Chikv的抵抗。由于DENV和CHIKV都 蚊子的适应性减少，它们有可能充当人群中的选择性力量 他们发生。奇克夫（Chikv 蚊子比Denv。在AIM 1中，我们采用实验进化方法来了解相对 与DENV相比，蚊子进化对CHIKV的潜力。在进化的线路中，我们将使用 全基因组缔合以识别支撑病毒抗性的候选SNP/基因。使用有效 CRISPR-CAS9方法专门为AE开发。埃及，我们可以测试功能参与 抗性的顶级候选基因。在AIM 2中，我们探讨了通用套件的功能重要性 全球存在于CHIKV包膜蛋白编码基因（E2）中的变体。 E2媒体进入 蚊子组织和基因的变化会影响载体的传播。在完成这些目标时，我们 将生成新工具并在新环境中应用新兴工具，包括改进的使用 蚊子中的荧光记者病毒，而不是体外和“矢量”载体的适应 与CHIKV和AE一起使用的能力系统。白化病。我们将解决的关键知识差距 是（i）如果chikv 随着时间的推移，传播可能会发展到较低的水平，（ii）潜在的抗chikv和共享抗的列表 CHIKV和DENV蚊子基因靶向遗传修饰方法，以及（iii）理解 关于CHIKV基因组中循环的E2变体如何塑造蚊子感染和全球景观 Chikv流行病学。