The heat shock response restricts virus infection in Drosophila

Abstract

Innate immunity is the first line of defence against pathogens and is essential for survival of the infected host. The fruit fly Drosophila melanogaster is an emerging model to study viral pathogenesis, yet antiviral defence responses remain poorly understood. Here, we describe the heat shock response, a cellular mechanism that prevents proteotoxicity, as a component of the antiviral immune response in Drosophila. Transcriptome analyses of Drosophila S2 cells and adult flies revealed strong induction of the heat shock response upon RNA virus infection. Dynamic induction patterns of heat shock pathway components were characterized in vitro and in vivo following infection with different classes of viruses. The heat shock transcription factor (Hsf), as well as active viral replication, were necessary for the induction of the response. Hsf-deficient adult flies were hypersensitive to virus infection, indicating a role of the heat shock response in antiviral defence. In accordance, transgenic activation of the heat shock response prolonged survival time after infection and enabled long-term control of virus replication to undetectable levels. Together, our results establish the heat shock response as an important constituent of innate antiviral immunity in Drosophila.

Fever as an important resource for infectious diseases research

“…They have been described in a range of species (40,44,46), including vertebrates (41) and among those, humans (47). Lack of the 70-kilodalton family of HSPs (HSP70), a highly conserved protein promoter of heat tolerance (46), induces heat shock sensitivity in E. coli strains that would be otherwise resistant to that type of stress.…”

“…At a deeper molecular level, heat-shock proteins (HSPs) (38,39), are a set of genetically conserved stress sensitive proteins (39) that accumulate in cases of exposure to high temperatures (35,(40)(41)(42)(43), among other sets of stressful conditions, in order to protect the cell (44), potentially by aiding in correct folding of proteins denatured by heat shock (35,45). They have been described in a range of species (40,44,46), including vertebrates (41) and among those, humans (47).…”

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

“…Infection of S2 cells or adult flies with DCV results in the induction of 6 genes encoding various heat-shock proteins (Hsp70Ab, Hsp70Ba, Hsp22, Hsp23, Hsp26, Hsp27) [168]. Also CrPV infections result in the induction of heat-shock protein genes but with delayed kinetics, while for a IIV-6 a clear heat-shock response is observed in S2 cells but not in adult flies.…”

“…Also CrPV infections result in the induction of heat-shock protein genes but with delayed kinetics, while for a IIV-6 a clear heat-shock response is observed in S2 cells but not in adult flies. Furthermore, flies mutant for Heat shock transcription factor (Hsf) or transgenic flies with fatty body-specific knockdown of Hsf are more sensitive to viral infection [168]. The heat-shock response acts independently of RNAi or Jak-STAT pathway since no interference with RNAi-mediated silencing or antiviral gene induction is observed in Hsf mutants or knockdown animals.…”

“…Virus infection often results in the generation of secondary transcriptional responses in other tissues that are mediated by systemic signals [145]. Activation of the JAK/STAT pathway (vir-1, Turandot proteins) likely is a secondary response caused by tissue damage and stress signals associated with viral replication [151,162,168]. Unique responses can also be generated by pathological effects by the virus, for instance during intestinal obstruction caused by DCV infection [169].…”