Drosophila have been used to model infections by viruses of the Flaviviridae genus, a group of arthropod-borne viruses (arboviruses). Flaviviruses can be roughly grouped into tick-borne and mosquito-borne, the latter group including dengue, Japanese encephalitis, West Nile virus, yellow fever, and Zika virus among others. Unlike related viruses, insect-borne flaviviruses can also infect vertebrate species, including birds and mammals. Flaviviruses have been responsible for many notorious epidemics in warm climates across the world, and their study has contributed much to our understanding of viruses as infectious agents.
Drosophila cell culture provides a way to perform high-throughput screens for response to flavivirus infection. Internalization of West Nile virus relies on the ribonuclease RNASEK, shown first in Drosophila S1 (DL1) cells and then in human osteosarcoma cells. Dengue virus replicates in S2 cells, and its replication rate is increased by knocking down components of the RNAi pathway, including Dcr-2 and AGO2.
Work in Drosophila has identified components of the response to flaviviruses that are conserved in humans. Depletion of Spase12 and Spase22-23, two components of the signal peptidase complex, causes a reduction in West Nile viral load both in cell culture and in adult Drosophila. In humans, reduction of the Spase12 ortholog SPCS1 also prevents infection of 293T cells by West Nile virus. Similarly, pont and emb have broadly antiviral activity in Drosophila cell culture and adults, as well as mosquitoes and humans.
The Drosophila response to Zika relies on IMD and NF-κB pathway members including PGRP-LC, PGRP-LE, Rel, DptA, and downstream target Sting. Zika-infected brains showed increased autophagy, and loss of autophagy effectors also increased the amount of Zika RNA in the brain. Flies can be protected against Zika infection by treatment with rapamycin, which activates autophagy. There is conflicting evidence concerning whether the loss of RNAi effectors Dcr-2 and AGO2 do (FBrf0240586) or do not (FBrf0239425) affect the course of Zika infection, as well as where the greatest concentration of Zika virus particles is inside the fly body.
Rare disorders associated with Zika infection include Guillain-Barre syndrome (DOID:12842) and Zika virus-related microcephaly (FBhh0001035). Expression of the Zika virus protein ZIKV\NS4A in Drosophila larvae heterozygous for a hypomorphic allele of Ankle2 caused a decrease in the volume of third instar larval brains, similar to the microcephaly phenotype caused by homozygous loss of Ankle2; see FBhh0001035 for further details.
The dengue virus genes DENV\NS3 and DENV\NS4A have been introduced into Drosophila; flies expressing DENV\NS3 it are more susceptible to infection by pathogenic strains of Staphylococcus aureus (FBhh0001078) and Pseudomonas aeruginosa (FBhh0000863).
[updated Jan 2020 by FlyBase; FBrf0222196]
Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. (Gould and Solomon 2008, pubmed:18262042.)
Viruses in the genus Flavivirus differ from other members of the family Flaviviridae in their antigenic, ecological, and epidemiological characteristics. Many of the flaviviruses have been shown to infect both vertebrate and invertebrate species, a feature not common to viruses in other genera of the family. (Gould et al. 2003, pubmed:14696332.)
The flaviviral genome is a positive-strand RNA that contains a type I cap at its 5' end and characteristically lacks a poly-A tail at its 3' end. The viral genome encodes a single polyprotein that is co- and post-translationally cleaved by viral and host proteases into 10 mature viral proteins (C, prM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). (Adapted from Barrows et al. 2018, pubmed:29652486.)
In mammals, flaviviruses induce the ER stress response and pro-apoptotic signaling, although the molecular targets vary among flaviviruses. (Adapted from Okamoto et al. 2017, pubmed:28846635)
