Australian Infectious Disease Research Centre, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia.
Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10276-81. doi: 10.1073/pnas.1303603110. Epub 2013 Jun 3.
The endosymbiont Wolbachia is common among insects and known for the reproductive manipulations it exerts on hosts as well as inhibition of virus replication in their hosts. Recently, we showed that Wolbachia uses host microRNAs to manipulate host gene expression for its efficient maintenance in the dengue mosquito vector, Aedes aegypti. Cytosine methylation is mediated by a group of proteins called DNA (cytosine-5) methyltransferases, which are structurally and functionally conserved from prokaryotes to eukaryotes. The biological functions of cytosine methylation include host defense, genome stability, gene regulation, developmental promotion of organs, and lifespan regulation. Ae. aegypti has only one DNA methyltransferase gene (AaDnmt2) belonging to the cytosine methyltransferase family 2, which is the most deeply conserved and widely distributed gene among metazoans. Here, we show that in mosquitoes the introduced endosymbiont, Wolbachia, significantly suppresses expression of AaDnmt2, but dengue virus induces expression of AaDnmt2. Interestingly, we found that aae-miR-2940 microRNA, which is exclusively expressed in Wolbachia-infected mosquitoes, down-regulates the expression of AaDnmt2. Reversely, overexpression of AaDnmt2 in mosquito cells led to inhibition of Wolbachia replication, but significantly promoted replication of dengue virus, suggesting a causal link between this Wolbachia manipulation and the blocking of dengue replication in Wolbachia-infected mosquitoes. In addition, our findings provide an explanation for hypomethylation of the genome in Wolbachia-infected Ae. aegypti.
共生菌沃尔巴克氏体在昆虫中很常见，其以对宿主的生殖操纵以及抑制宿主病毒复制而闻名。最近，我们发现沃尔巴克氏体利用宿主 microRNA 来操纵宿主基因表达，从而使其在登革热蚊子载体埃及伊蚊中得到有效维持。胞嘧啶甲基化由一组称为 DNA（胞嘧啶-5）甲基转移酶的蛋白质介导，这些蛋白质在原核生物到真核生物中结构和功能都保守。胞嘧啶甲基化的生物学功能包括宿主防御、基因组稳定性、基因调控、器官发育促进和寿命调节。埃及伊蚊只有一个 DNA 甲基转移酶基因（AaDnmt2），属于胞嘧啶甲基转移酶家族 2，这是后生动物中最保守和广泛分布的基因。在这里，我们表明，在蚊子中，引入的共生菌沃尔巴克氏体显著抑制 AaDnmt2 的表达，但登革热病毒诱导 AaDnmt2 的表达。有趣的是，我们发现一种仅在感染沃尔巴克氏体的蚊子中表达的 aae-miR-2940 microRNA 下调 AaDnmt2 的表达。相反，蚊细胞中 AaDnmt2 的过表达导致沃尔巴克氏体复制受到抑制，但显著促进登革热病毒的复制，这表明这种沃尔巴克氏体操纵与沃尔巴克氏体感染蚊子中登革热病毒复制的阻断之间存在因果关系。此外，我们的发现为感染沃尔巴克氏体的埃及伊蚊基因组低甲基化提供了一种解释。
