ATPsensitive potassium channels and resistance to virus infection

How does the inducible antiviral response contribute to the pathogenesis of the infection? In mammals, inflammatory cytokines, such as tumour necrosis factor (TNF), trigger inflammation by acting on blood vessels (i.e. vasodilatation) and the systemic effects of TNF can lead to septic shock. Could there be a similar situation in flies? Recent genetic data suggest that this might be the case. These studies were initiated by the identification of the mayday mutation in mice, which leads to increased sensitivity to infection with the DNA virus mouse cytomegalovirus (MCMV). Strikingly, mayday mutant mice die abruptly 2-3 days after infection, without showing any signs of overt disease, and when viral titres are still fairly low. Induction of interferons and other inflammatory cytokines is not affected in mayday mutant mice, indicating that these animals do not appear to be conventionally immunocompromised, and viral titres in mutant and wild-type mice are comparable at the time of death of mayday mutant mice. Chromosomal mapping and positional cloning pinpointed the Kcnj8

gene as the target of the mayday mutation. Kcnj8 encodes Kir6.1, the pore-forming component of an inwardly rectifying ATP-sensitive potassium channel (KATP) that is expressed in coronary artery smooth muscle cells. This channel also incorporates the regulatory subunit SUR2 (sulphonylu-rea receptor 2). Altogether these data highlight the important role of KATP channels in modulation of cardiovascular stress during the immune response to infections (Croker et al, 2007) (Figure 4.5).

Katp channels are evolutionary conserved, and Drosophila has two orthologues (Ir and Irk2) of the gene encoding the potassium channel pore, but only a single orthologue of the gene encoding the regulatory subunit (SUR2) of the mammalian potassium channel. Of note, this gene, called

Drosophila SUR (dSUR), is mainly expressed in the contractile dorsal vessel that forms the Drosophila heart. Moreover, dSUR has a protective role against hypoxic stress and heart failure induced by electrical pacing (Akasaka et al,, 2006). This may have relevance for resistance to viral infection, since sensitivity to hypoxia is a readout for the susceptibility to two Drosophila viruses, SIGMAV and DXV. These findings led us to test the role of dSUR in the resistance to virus infection in flies. Silencing of dSUR expression in the Drosophila heart, but not in other tissues, was found to result in increased susceptibility to challenge with FHV. By contrast, dSUR knock-down flies experienced mortality similar to that of wild-type controls when infected with DCV or the bacterial pathogens Enterococcus

Mouse

MCMV

Drosophila

Haematopoietic cell

Mouse

MCMV

Haematopoietic cell

Drosophila Fat Body

Vasodilatation

PRRs?

Drosophila

PRRs?

Fat body cell

Cytokines ?

Cytokines ?

Modification of cardiac activity?

Vasodilatation

Modification of cardiac activity?

Figure 4.5 Model for the role of ATP-sensitive potassium channels (KATP) in the resistance to virus infection. In mice, cytokines produced in virus-infected cells act on blood vessels and trigger vasoconstriction. This effect is opposed by KATP channels, which are composed of a pore subunit and a regulatory subunit (Kir6.1 and SUR2 in coronary arteries). By analogy, KATP channels in Drosophila may counteract cytokine-mediated effects on the dorsal vessel of FHV-infected cells, thus explaining why Drosophila SUR (dSUR) expression in cardiomyocytes is required to resist infection by this virus. FHV, Flock House virus; Kir6.1, inwardly rectifying KATP; MCMV, mouse cytomegalovirus; PRRs, pattern-recognition receptors; SUR2, sulphonylurea receptor 2; TLRs, Toll-like receptors.

faecelis, Enterobacter cloacae, or the fungus Beauveria bassiana. In addition, treatment of wild-type flies with tolbutamide, an antagonist of the channel, also affects resistance to FHV (Croker et al, 2007).

These findings provide further evidence that both insects and mammals rely on a common homeostatic mechanism for protection against viruses, and open the way for future studies aimed at elucidating the exact role of KATP channels in the physiology of viral infections.

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