Discovery of insect and human dengue virus host factors

Abstract

Dengue fever is endemic in many countries in South and Southeast Asia, Africa and South America, and elsewhere it is an emerging threat. It is caused by one of four dengue viruses — DENV-1, 2, 3 and 4 — transmitted by Aedes sp. mosquitoes; there is no approved vaccine and no effective specific therapy. The dengue viruses are compact flaviviruses likely to require a large number of host factors, and knowledge of those factors could lead to the discovery of potential targets for drugs and new vector control strategies. Now by using a high-throughput RNAi screening approach in DENV-2-infected Drosophila cells — Drosophila is related to the vector species and more amenable to the tools of genomics — more than a hundred candidate dengue virus host factors have been identified, many of them also acting as host factors in human cells. This report identifies host factors required for Dengue virus propagation by using a high throughput genome-wide RNA interference screening approach in Drosophila cells. Dengue fever is the most frequent arthropod-borne viral disease of humans, with almost half of the world’s population at risk of infection1. The high prevalence, lack of an effective vaccine, and absence of specific treatment conspire to make dengue fever a global public health threat1,2. Given their compact genomes, dengue viruses (DENV-1–4) and other flaviviruses probably require an extensive number of host factors; however, only a limited number of human, and an even smaller number of insect host factors, have been identified3,4,5,6,7,8,9,10. Here we identify insect host factors required for DENV-2 propagation, by carrying out a genome-wide RNA interference screen in Drosophila melanogaster cells using a well-established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses (for example, V-ATPases and α-glucosidases)3,4,5,7,9,10, most of the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologues and, using a targeted short-interfering-RNA screen, we showed that 42 of these are human DVHFs. This indicates notable conservation of required factors between dipteran and human hosts. This work suggests new approaches to control infection in the insect vector and the mammalian host.