Arboviruses and apoptosis: the role of cell death in determining vector competence

Clem, Rollie J.

doi:10.1099/jgv.0.000429

Cited by 42 publications

(38 citation statements)

References 31 publications

(33 reference statements)

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“…Accordingly, flies with mutations for the Jak kinase Hopscotch are susceptible to infection by Drosophila C virus (DCV) and Cricket paralysis virus (CrPV), two members of the Dicistroviridae family, although they are as resistant as wild-type controls to other viruses (e.g., the alphavirus Sindbis virus [SINV] or the rhabdovirus vesicular stomatitis virus [VSV]) (3). Virus-induced autophagy and apoptosis have also been associated with antiviral immunity in Drosophila (22)(23)(24) and other insects (reviewed in reference 25).…”

Section: Importancementioning

confidence: 99%

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Lamiable

Arnold

Faria

et al. 2016

J Virol

112

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Antiviral immunity in the model organism Drosophila melanogaster involves the broadly active intrinsic mechanism of RNA interference (RNAi) and virus-specific inducible responses. Here, using a panel of six viruses, we investigated the role of hemocytes and autophagy in the control of viral infections. Injection of latex beads to saturate phagocytosis, or genetic depletion of hemocytes, resulted in decreased survival and increased viral titers following infection with Cricket paralysis virus (CrPV), Flock House virus (FHV), and vesicular stomatitis virus (VSV) but had no impact on Drosophila C virus (DCV), Sindbis virus (SINV), and Invertebrate iridescent virus 6 (IIV6) infection. In the cases of CrPV and FHV, apoptosis was induced in infected cells, which were phagocytosed by hemocytes. In contrast, VSV did not trigger any significant apoptosis but we confirmed that the autophagy gene Atg7 was required for full virus resistance, suggesting that hemocytes use autophagy to recognize the virus. However, this recognition does not depend on the Toll-7 receptor. Autophagy had no impact on DCV, CrPV, SINV, or IIV6 infection and was required for replication of the sixth virus, FHV. Even in the case of VSV, the increases in titers were modest in Atg7 mutant flies, suggesting that autophagy does not play a major role in antiviral immunity in Drosophila. Altogether, our results indicate that, while autophagy plays a minor role, phagocytosis contributes to virus-specific immune responses in insects. IMPORTANCEPhagocytosis and autophagy are two cellular processes that involve lysosomal degradation and participate in Drosophila immunity. Using a panel of RNA and DNA viruses, we have addressed the contribution of phagocytosis and autophagy in the control of viral infections in this model organism. We show that, while autophagy plays a minor role, phagocytosis contributes to virusspecific immune responses in Drosophila. This work brings to the front a novel facet of antiviral host defense in insects, which may have relevance in the control of virus transmission by vector insects or in the resistance of beneficial insects to viral pathogens.

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Section: Importancementioning

confidence: 99%

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Lamiable

Arnold

Faria

et al. 2016

J Virol

112

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“…In arthropods, antiviral responses are predominantly mediated by RNAi (13,15), and also by Toll, IMD, and JAK/STAT signaling pathways and apoptosis (16,17). Three distinct insect small-RNA pathways can be discriminated: the 21-nucleotide (nt) small interfering RNA (siRNA) response, the ϳ21-to 22-nt microRNA (miRNA) pathway, and the 25-to 30-nt PIWI-interacting RNA (piRNA) response (18)(19)(20).…”

mentioning

confidence: 99%

Noncoding Subgenomic Flavivirus RNA Is Processed by the Mosquito RNA Interference Machinery and Determines West Nile Virus Transmission by Culex pipiens Mosquitoes

Göertz

Fros

Miesen

et al. 2016

J Virol

114

163

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Flaviviruses, such as Zika virus, yellow fever virus, dengue virus, and West Nile virus (WNV), are a serious concern for human health. Flaviviruses produce an abundant noncoding subgenomic flavivirus RNA (sfRNA) in infected cells. sfRNA results from stalling of the host 5=-3= exoribonuclease XRN1/Pacman on conserved RNA structures in the 3= untranslated region (UTR) of the viral genomic RNA. sfRNA production is conserved in insect-specific, mosquito-borne, and tick-borne flaviviruses and flaviviruses with no known vector, suggesting a pivotal role for sfRNA in the flavivirus life cycle. Here, we investigated the function of sfRNA during WNV infection of Culex pipiens mosquitoes and evaluated its role in determining vector competence. An sfRNA1-deficient WNV was generated that displayed growth kinetics similar to those of wild-type WNV in both RNA interference (RNAi)-competent and -compromised mosquito cell lines. Small-RNA deep sequencing of WNV-infected mosquitoes indicated an active small interfering RNA (siRNA)-based antiviral response for both the wild-type and sfRNA1-deficient viruses. Additionally, we provide the first evidence that sfRNA is an RNAi substrate in vivo. Two reproducible small-RNA hot spots within the 3= UTR/sfRNA of the wild-type virus mapped to RNA stem-loops SL-III and 3= SL, which stick out of the three-dimensional (3D) sfRNA structure model. Importantly, we demonstrate that sfRNA-deficient WNV displays significantly decreased infection and transmission rates in vivo when administered via the blood meal. Finally, we show that transmission and infection rates are not affected by sfRNA after intrathoracic injection, thereby identifying sfRNA as a key driver to overcome the mosquito midgut infection barrier. This is the first report to describe a key biological function of sfRNA for flavivirus infection of the arthropod vector, providing an explanation for the strict conservation of sfRNA production. IMPORTANCEUnderstanding the flavivirus transmission cycle is important to identify novel targets to interfere with disease and to aid development of virus control strategies. Flaviviruses produce an abundant noncoding viral RNA called sfRNA in both arthropod and mammalian cells. To evaluate the role of sfRNA in flavivirus transmission, we infected mosquitoes with the flavivirus West Nile virus and an sfRNA-deficient mutant West Nile virus. We demonstrate that sfRNA determines the infection and transmission rates of West Nile virus in Culex pipiens mosquitoes. Comparison of infection via the blood meal versus intrathoracic injection, which bypasses the midgut, revealed that sfRNA is important to overcome the mosquito midgut barrier. We also show that sfRNA is processed by the antiviral RNA interference machinery in mosquitoes. This is the first report to describe a pivotal biological function of sfRNA in arthropods. The results explain why sfRNA production is evolutionarily conserved. Viruses from the genus Flavivirus (family Flaviviridae), such as the highly pathogenic dengue virus (DENV...

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“…RNAi) can reduce the levels of viral replication and damage to the point where they are not pro-apoptotic (as seems to be the case for SINV). Nevertheless, the importance of apoptosis to control viral infections was demonstrated by recombinant SINV viruses that express the pro-apoptotic gene reaper [181]. Viruses expressing a pro-apoptotic gene were selected against to establish persistent infections in mosquitoes, presumably because of the strong antiviral effect of the pro-apoptotic gene [182].…”

Section: Cellular Responses Against Viral Infections: Phagocytosis Amentioning

confidence: 99%

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

Swevers¹,

Liu²,

Smagghe³

2018

Preprint

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RNAi is considered a major antiviral defense mechanism in insects but its relative importance compared to other antiviral pathways has not been evaluated comprehensively. Here, it is attempted to give an overview of the antiviral defense mechanisms in Drosophila that involve both RNAi and non-RNAi to acquire a sense of their relative importance. While RNAi is considered important in most viral infections, many other pathways can exist that confer antiviral resistance. It is noted that very few direct recognition mechanisms of virus infections have been identified in Drosophila and that the activation of immune pathways may be accomplished indirectly through cell damage incurred by viral replication. In several cases, protection against viral infection can be obtained in RNAi mutants by non-RNAi mechanisms, confirming the variability of the RNAi defense mechanism according to the type of infection and the physiological status of the host. This analysis invites to investigate more systematically the relative contribution of RNAi in the antiviral response and more specifically to ask whether RNAi efficiency is affected when other defense mechanisms predominate. While Drosophila can function as a useful model, this issue may be more critical for economically important insects that are either controlled (agricultural pests and vectors of diseases) or protected from parasite infection (beneficial insects as bees) by RNAi products.

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Arboviruses and apoptosis: the role of cell death in determining vector competence

Cited by 42 publications

References 31 publications

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Noncoding Subgenomic Flavivirus RNA Is Processed by the Mosquito RNA Interference Machinery and Determines West Nile Virus Transmission by Culex pipiens Mosquitoes

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

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