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

Abstract

The effects of the cellular environment on innate immunity remain poorly characterized. Here, we show that in Drosophila ATP-sensitive potassium channels (K(ATP)) mediate resistance to a cardiotropic RNA virus, Flock House virus (FHV). FHV viral load in the heart rapidly increases in K(ATP) mutant flies, leading to increased viremia and accelerated death. The effect of K(ATP) channels is dependent on the RNA interference genes Dcr-2, AGO2, and r2d2, indicating that an activity associated with this potassium channel participates in this antiviral pathway in Drosophila. Flies treated with the K(ATP) agonist drug pinacidil are protected against FHV infection, thus demonstrating the importance of this regulation of innate immunity by the cellular environment in the heart. In mice, the Coxsackievirus B3 replicates to higher titers in the hearts of mayday mutant animals, which are deficient in the Kir6.1 subunit of K(ATP) channels, than in controls. Together, our data suggest that K(ATP) channel deregulation can have a critical impact on innate antiviral immunity in the heart.

Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: A novel role in egg production

“…Alternatively, it is possible that (1) other Kir channels expressed in the Malpighian tubules of A. gambiae can compensate for the reduced levels of AgKir1, (2) Kir1 performs different functions in the Malpighian tubules of A. gambiae and A. aegypti , or (3) RNAi efficiency is markedly different between tissues (Boisson et al, 2006). Nevertheless, our survival experiment is consistent with studies in D. melanogaster , where there is no apparent lethal effect following Kir1 knockdown, but rather a sub-lethal effect on immune function (Eleftherianos et al, 2011). …”

Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: A novel role in egg production

“…Alternatively, it is possible that (1) other Kir channels expressed in the Malpighian tubules of A. gambiae can compensate for the reduced levels of AgKir1, (2) Kir1 performs different functions in the Malpighian tubules of A. gambiae and A. aegypti , or (3) RNAi efficiency is markedly different between tissues (Boisson et al, 2006). Nevertheless, our survival experiment is consistent with studies in D. melanogaster , where there is no apparent lethal effect following Kir1 knockdown, but rather a sub-lethal effect on immune function (Eleftherianos et al, 2011). …”

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

“…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.…”

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling

“…More widely, few reports exist of a dependence on host K ATP channel activity for viral replication. One study identified that inhibition of K ATP channels via glibenclamide treatment precludes HIV cell entry but, in contrast, cardiac K ATP channel activity was found to be detrimental to Flock House virus (FHV) infection of Drosophila [63, 64]. Significantly however, no evidence exists to suggest that either of these viruses actively modulate the gating and/or expression of these channels, as we have demonstrated for HPV here.…”

Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: A novel role in egg production

“…Alternatively, it is possible that (1) other Kir channels expressed in the Malpighian tubules of A. gambiae can compensate for the reduced levels of AgKir1, (2) Kir1 performs different functions in the Malpighian tubules of A. gambiae and A. aegypti , or (3) RNAi efficiency is markedly different between tissues (Boisson et al, 2006). Nevertheless, our survival experiment is consistent with studies in D. melanogaster , where there is no apparent lethal effect following Kir1 knockdown, but rather a sub-lethal effect on immune function (Eleftherianos et al, 2011). …”

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

“…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.…”

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling

“…More widely, few reports exist of a dependence on host K ATP channel activity for viral replication. One study identified that inhibition of K ATP channels via glibenclamide treatment precludes HIV cell entry but, in contrast, cardiac K ATP channel activity was found to be detrimental to Flock House virus (FHV) infection of Drosophila [63, 64]. Significantly however, no evidence exists to suggest that either of these viruses actively modulate the gating and/or expression of these channels, as we have demonstrated for HPV here.…”

Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: A novel role in egg production

“…Alternatively, it is possible that (1) other Kir channels expressed in the Malpighian tubules of A. gambiae can compensate for the reduced levels of AgKir1, (2) Kir1 performs different functions in the Malpighian tubules of A. gambiae and A. aegypti , or (3) RNAi efficiency is markedly different between tissues (Boisson et al, 2006). Nevertheless, our survival experiment is consistent with studies in D. melanogaster , where there is no apparent lethal effect following Kir1 knockdown, but rather a sub-lethal effect on immune function (Eleftherianos et al, 2011). …”

Drosophila C Virus Systemic Infection Leads to Intestinal Obstruction

“…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.…”

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling

“…More widely, few reports exist of a dependence on host K ATP channel activity for viral replication. One study identified that inhibition of K ATP channels via glibenclamide treatment precludes HIV cell entry but, in contrast, cardiac K ATP channel activity was found to be detrimental to Flock House virus (FHV) infection of Drosophila [63, 64]. Significantly however, no evidence exists to suggest that either of these viruses actively modulate the gating and/or expression of these channels, as we have demonstrated for HPV here.…”