ATP-sensitive potassium channel (K
            <sub>ATP</sub>
            )–dependent regulation of cardiotropic viral infections

Eleftherianos, Ioannis; Won, Sungyong; Chtarbanova, Stanislava; Squiban, Barbara; Ocorr, Karen; Bodmer, Rolf; Beutler, Bruce; Hoffmann, Jules A.; Imler, Jean Luc

doi:10.1073/pnas.1108926108

Cited by 59 publications

(70 citation statements)

References 34 publications

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“…We further show that the major symptoms result from the tissue tropism of DCV for the crop muscles. These results complement our previous study demonstrating that the sensitivity of flies defective for K ATP channels to FHV, but not DCV, infection results from the tropism of FHV for the cardiomyocytes in the dorsal vessel (22). Altogether, these studies reveal that two small nonenveloped positive-sense RNA viruses sharing the ability to replicate rapidly in flies, killing them within a week or so (25), trigger different pathophysiological events.…”

Section: Discussionsupporting

confidence: 77%

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Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Chtarbanova

Lamiable

Lee

et al. 2014

J Virol

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Drosophila C virus (DCV) is a positive-sense RNA virus belonging to the Dicistroviridae family. This natural pathogen of the model organism Drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both RNA interference and inducible responses. Although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. Here, we characterize the pathogenesis associated with systemic DCV infection. Comparison of the transcriptome of flies infected with DCV or two other positive-sense RNA viruses, Flock House virus and Sindbis virus, reveals that DCV infection, unlike those of the other two viruses, represses the expression of a large number of genes. Several of these genes are expressed specifically in the midgut and also are repressed by starvation. We show that systemic DCV infection triggers a nutritional stress in Drosophila which results from intestinal obstruction with the accumulation of peritrophic matrix at the entry of the midgut and the accumulation of the food ingested in the crop, a blind muscular food storage organ. The related virus cricket paralysis virus (CrPV), which efficiently grows in Drosophila, does not trigger this pathology. We show that DCV, but not CrPV, infects the smooth muscles surrounding the crop, causing extensive cytopathology and strongly reducing the rate of contractions. We conclude that the pathogenesis associated with systemic DCV infection results from the tropism of the virus for an important organ within the foregut of dipteran insects, the crop. IMPORTANCEDCV is one of the few identified natural viral pathogens affecting the model organism Drosophila melanogaster. As such, it is an important virus for the deciphering of host-virus interactions in insects. We characterize here the pathogenesis associated with DCV infection in flies and show that it results from the tropism of the virus for an essential but poorly characterized organ in the digestive tract, the crop. Our results may have relevance for other members of the Dicistroviridae, some of which are pathogenic to beneficial or pest insect species.

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Section: Discussionsupporting

confidence: 77%

“…However, virus-induced pathologies in flies still are poorly understood (21,22). Here, we have investigated an aspect of the pathology caused by DCV, a natural pathogen of Drosophila frequently used to investigate antiviral immunity.…”

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confidence: 99%

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Chtarbanova

Lamiable

Lee

et al. 2014

J Virol

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“…The Drosophila genome encodes three inwardly rectifying K ϩ channels, Irk1 (also called Ir, Dir, or DrKir1), Irk2 (also called DrKir2), and Irk3 (also called dKirIII or DrKir3) (7,20,23). Roles for Irk genes have been described in wing development (4) and cardiotropic viral infections (10). In addition, all three Irk genes are expressed in the principal cell of the Malpighian tubule, and pharmacological experiments using sulphonylureas have suggested a role for Irk channels in tubule function (11).…”

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confidence: 99%

Two inwardly rectifying potassium channels,Irk1andIrk2, play redundant roles inDrosophilarenal tubule function

Baum

Huang

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Inwardly rectifying potassium channels play essential roles in renal physiology across phyla. Bariumsensitive K ϩ conductances are found on the basolateral membrane of a variety of insect Malpighian (renal) tubules, including Drosophila melanogaster. We found that barium decreases the lumen-positive transepithelial potential difference in isolated perfused Drosophila tubules and decreases fluid secretion and transepithelial K ϩ flux. In those insect species in which it has been studied, transcripts from multiple genes encoding inwardly rectifying K ϩ channels are expressed in the renal (Malpighian) tubule. In Drosophila melanogaster, this includes transcripts of the Irk1, Irk2, and Irk3 genes. The role of each of these gene products in renal tubule function is unknown. We found that simultaneous knockdown of Irk1 and Irk2 in the principal cell of the fly tubule decreases transepithelial K ϩ flux, with no additive effect of Irk3 knockdown, and decreases barium sensitivity of transepithelial K ϩ flux by ϳ50%. Knockdown of any of the three inwardly rectifying K ϩ channels individually has no effect, nor does knocking down Irk3 simultaneously with Irk1 or Irk2. Irk1/Irk2 principal cell double-knockdown tubules remain sensitive to the kaliuretic effect of cAMP. Inhibition of the Na ϩ /K ϩ -ATPase with ouabain and Irk1/Irk2 double knockdown have additive effects on K ϩ flux, and 75% of transepithelial K ϩ transport is due to Irk1/Irk2 or ouabain-sensitive pathways. In conclusion, Irk1 and Irk2 play redundant roles in transepithelial ion transport in the Drosophila melanogaster renal tubule and are additive to Na ϩ /K ϩ -ATPase-dependent pathways.Malpighian tubule; epithelial ion transport; barium; Kir; Ir; Dir; dKirIII; ion-specific electrode; Ramsay assay INWARDLY RECTIFYING POTASSIUM CHANNELS play key roles in vertebrate and invertebrate renal physiology and epithelial ion transport (13, 27, 28, 31, 32, 36 -38, 43, 44, 47). Mutations in KCNJ1/Kir1.1 (also known as renal outer medullary K ϩ channel, or ROMK) and KCNJ10/Kir4.1 result in human diseases characterized by salt-losing tubulopathies and electrolyte disturbances (1,40,42). Inwardly rectifying K ϩ channels also play important roles in insect iono-and osmoregulation. For example, in mosquitoes, pharmacological inhibition of inwardly rectifying K ϩ channels decreases renal tubule fluid secretion and alters both transepithelial ion fluxes in the tubule as well as whole-body ion clearances and urine excretion (28,31,32,36,38,41). This results in decreased viability and flight capacity (31,32,38). As such, inwardly rectifying K ϩ channels are potential targets for insecticidal agents.

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“…Understanding FHV progression following the oral route of infection would be invaluable in identifying the tissues that are important in primary FHV infection, however no such studies have been performed to date. Following systemic FHV infection, FHV has been observed in the cardiomyocytes (38), fat body and salivary glands (12), however FHV localization may not be confined to the above-mentioned tissues.…”

Section: Reaper-mediated Protectionmentioning

confidence: 99%

“…Recognition of pathogens through the siRNA pathway occurs through recognition of double-stranded viral RNA intermediates by Dicer-2 ( Figure 1) (33). Dicer-2 processes dsRNAs into small siRNAs fragments 21 nucleotides long (36,37 Dicer-2 or other components of the machinery to avoid processing (29,31,38,41,42).…”

Section: Rna Interference Pathway (Rnai)mentioning

confidence: 99%

Characterization of infection in Drosophila following oral challenge with the Drosophila C virus and Flock House virus

Stevanovic¹

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Understanding antiviral processes in infected organisms is of great importance when designing tools targeted at alleviating the burden viruses have on our health and society. Our understanding of innate immunity has greatly expanded in the last 10 years, and some of the biggest advances came from studying pathogen protection in the model organism Drosophila melanogaster. Several antiviral pathways have been found to be involved in antiviral protection in Drosophila however the molecular mechanisms behind antiviral protection have been largely unexplored and poorly characterized. Host-virus interaction studies in Interestingly, Wolbachia-mediated protection was life-stage dependent as oral feeding of L1stage larvae resulted in a loss of Wolbachia-mediated protection in 3 out of 4 DrosophilaWolbachia associations shown to be protective at the adult stages. Loss of protection was associated with lower Wolbachia densities at larval compared to adult stages in the same three Drosophila-Wolbachia associations. These results will aid in understanding the effects of Wolbachia on viral dynamics in natural populations and will contribute to our understanding of life-stage susceptibility in Drosophila.In the 4 th chapter the role of apoptosis in mediating antiviral protection was studied following both viral injections (systemic infection) and oral infections using FHV as a model.Using altered gene expression of key genes involved in apoptosis I investigated the importance of apoptosis on antiviral protection. Knocking-out a pro-apoptotic transcription factor dP53 in adult flies lead to an increase in viral titers following a systemic FHV infection and resulted in earlier mortality of infected individuals compared to wild type flies. Contrary to systemic infection, oral FHV infection of the same fly line showed no effect on viral accumulation but led to earlier mortality of infected individuals. Over-expressing a proapoptotic gene reaper lead to a reduction in FHV viral titers following both systemic and oral infections, however while a reduction in viral titers lead to a delay in virus-induced mortality in systemically infected flies, no differences in mortality was observed between wild type and mutant flies following oral infection. Oral infection with FHV caused 30 % mortality in both wild type and P53 and reaper over-expressing flies. The similarities in the number of flies succumbing to oral infection indicates that apoptosis does not impact the outcome of initial challenge, but that it likely functions in protection following primary infection. Depending on whether apoptosis was suppressed or enhanced lead to differences in the effects of apoptosis on resistance (ability of the host to control virus accumulation) and tolerance (ability of the host to endure infection), which lead to the idea that viral tissue tropism could be responsible for the differences in resistance versus tolerance.Taken together the results enhance our understanding of antiviral mechanisms in Drosophila and show that both the route of...

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ATP-sensitive potassium channel (K _ATP )–dependent regulation of cardiotropic viral infections

Cited by 59 publications

References 34 publications

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Two inwardly rectifying potassium channels,Irk1andIrk2, play redundant roles inDrosophilarenal tubule function

Characterization of infection in Drosophila following oral challenge with the Drosophila C virus and Flock House virus

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ATP-sensitive potassium channel (K ATP )–dependent regulation of cardiotropic viral infections

Cited by 59 publications

References 34 publications

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

Two inwardly rectifying potassium channels,Irk1andIrk2, play redundant roles inDrosophilarenal tubule function

Characterization of infection in Drosophila following oral challenge with the Drosophila C virus and Flock House virus

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ATP-sensitive potassium channel (K _ATP )–dependent regulation of cardiotropic viral infections