Dengue and chikungunya virus loads in the mosquito Aedes aegypti are determined by distinct genetic architectures.
Dengue and chikungunya virus loads in the mosquito Aedes aegypti are determined by distinct genetic architectures.
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DOI：
10.1371/journal.ppat.1011307
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发表时间：
2023-04
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
埃及伊蚊是虫媒病毒登革(DENV)和基孔肯雅(CHIKV)的主要媒介。这些病毒在媒介相互作用方面表现出关键的差异，后者在蚊子中移动更快，触发的标准抗病毒途径更少。随着CHIKV的全球足迹持续扩大，我们寻求更好地了解蚊子对CHIKV的自然反应--既要将其与DENV：媒介共同进化史进行比较，又要确定蚊子中进行基因改造的潜在靶点。我们使用一种改进的全同胞设计来估计蚊子基因变异对DENV和CHIKV病毒载量的贡献。遗传力显著，但DENV(40%)高于CHIKV(18%)。有趣的是，在兄弟姐妹之间，DENV和CHIKV载量之间没有遗传相关性。这些数据表明Ae.埃及伊蚊对这两种病毒的反应使用不同的遗传机制。我们还检查了代表病毒载量的表型极端的高和低CHIKV家族之间的全基因组基因表达模式。利用RNAseq，我们只确定了两个持续区分高和低家族的基因座：一个是在感染后的蚊子屏幕上发现的长的非编码RNA，另一个是唾液腺特异(SGS)基因家族的远程成员。有趣的是，后一种基因还与蚊子和内共生细菌沃尔巴克氏菌之间的水平基因转移有关。这项工作是首次将SGS基因与蚊子的表型联系起来。因此，了解这种基因如何在蚊子中对病毒控制做出贡献的分子细节，也可能有助于揭示它在沃尔巴克氏菌中的作用。导致人类长期关节炎症状的基孔肯雅病毒(CHIKV)是通过埃及伊蚊的叮咬传播的。目前还没有疫苗的CHIKV正在全球变得越来越普遍。因此，我们需要了解蚊子自身控制CHIKV的能力，因为我们可以利用这一知识通过基因改造创造出抗药性蚊子。我们发现，蚊子对CHIKV的遗传反应能力很低，这表明蚊子进化出抵抗力的可能性很低。我们还发现，CHIKV病毒载量的遗传基础似乎与另一种常见病毒登革热不同。因此，任何设计抗病毒蚊子的策略都可能需要针对病毒，或者专注于蚊子反应中的少数重叠基因。最后，当我们检查在高负载和低负载病毒谱系中表达不同的蚊子基因时，我们发现了一个在低负载家族中高表达的基因，因此，可能起到病毒控制器的作用。有趣的是，在沃尔巴克氏菌内共生菌的基因组中发现了该基因的同源基因，该细菌本身就是已知的限制其昆虫宿主内病毒复制的细菌。因此，应该在蚊子和沃尔巴克氏菌中探索这种同系物在病毒控制中的功能重要性。
Aedes aegypti is the primary vector of the arboviruses dengue (DENV) and chikungunya (CHIKV). These viruses exhibit key differences in their vector interactions, the latter moving more quicky through the mosquito and triggering fewer standard antiviral pathways. As the global footprint of CHIKV continues to expand, we seek to better understand the mosquito’s natural response to CHIKV—both to compare it to DENV:vector coevolutionary history and to identify potential targets in the mosquito for genetic modification. We used a modified full-sibling design to estimate the contribution of mosquito genetic variation to viral loads of both DENV and CHIKV. Heritabilities were significant, but higher for DENV (40%) than CHIKV (18%). Interestingly, there was no genetic correlation between DENV and CHIKV loads between siblings. These data suggest Ae. aegypti mosquitoes respond to the two viruses using distinct genetic mechanisms. We also examined genome-wide patterns of gene expression between High and Low CHIKV families representing the phenotypic extremes of viral load. Using RNAseq, we identified only two loci that consistently differentiated High and Low families: a long non-coding RNA that has been identified in mosquito screens post-infection and a distant member of a family of Salivary Gland Specific (SGS) genes. Interestingly, the latter gene is also associated with horizontal gene transfer between mosquitoes and the endosymbiotic bacterium Wolbachia. This work is the first to link the SGS gene to a mosquito phenotype. Understanding the molecular details of how this gene contributes to viral control in mosquitoes may, therefore, also shed light on its role in Wolbachia. The virus chikungunya (CHIKV) that causes long term arthritis symptoms in humans is transmitted to through the bite of the Aedes aegypti mosquito. CHIKV, for which there is no vaccine, is becoming increasingly common across the globe. We therefore need to understand the mosquito’s own ability to control CHIKV, as we may use that knowledge to create resistant mosquitoes through genetic modification. We show that the mosquito has very little ability to respond genetically to CHIKV, indicating low potential for the mosquito to evolve resistance. We also found that the genetic basis of CHIKV viral loads appears distinct from dengue, another common virus. As such, any strategy for engineering virus-resistant mosquitoes may need to be virus-specific or focus on the few overlapping genes in the mosquito response. Last, when we examined the mosquito genes whose expression differed between high and low-load virus lineages, we discovered a gene that was highly expressed in low-load families and therefore, potentially acting as a virus controller. Interestingly, a homolog of this gene has been discovered in the genome of the Wolbachia endosymbiont, itself known to limit virus replication inside its insect hosts. The functional importance of this homolog in virus control should therefore be explored in both mosquitoes and Wolbachia.
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