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ATP-sensitive potassium channels mediate survival during infection in mammals and insects

Abstract

Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea–mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and 20,000-fold sensitization to lipopolysaccharide (LPS), poly(I·C) and immunostimulatory (CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel (KATP) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, KATP evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/or MDA5 immunoreceptors.

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Figure 1: Responses of mayday mice to MCMV infection and to TLR stimuli ex vivo.
Figure 2: Genetic mapping and identification of mayday and slumber.
Figure 3: Progressive and sustained changes in heart gene expression in Kcnj8mydy/mydy mice after LPS injection.
Figure 4: dSUR is protective against FHV infection in Drosophila.

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Gene Expression Omnibus

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Acknowledgements

We thank For M.B.A. Oldstone and J.L. Whitton (TSRI) for IFN-β– and IFN-γ–deficient mice, respectively; R. Bodmer (The Burnham Institute for Medical Research, La Jolla, California, USA) for the UAS-dSUR RNAi lines and the GMH5-Gal4 driver line; and C. Galanos and M.A. Freudenberg (Max Planck Institut für Immunbiologie, Freiburg, Germany) for LPS-free poly(I·C). This work was supported by a grant from the National Institutes of Health (AI070167). M.B. was supported by an European Molecular Biology Organization Long-Term Fellowship. This is TSRI manuscript no. 18948.

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B. Croker identified the mayday mutant, positionally cloned the mutation, carried out much of the phenotypic analysis presented, and contributed to the writing of the paper. K. Crozat identified the slumber, solitaire and goodnight mutations, positionally identified slumber, and contributed to the phenotypic characterization of these mutants and the writing of the paper. M. Berger analyzed the TLF-mediated macrophage responses in mayday mutant mice. Y. Xia and S. Sovath contributed to the mapping and sequencing work and microarray analysis. L. Schaffer assisted with interpretation of microarray data. J. Imler and I. Eleftherianos studied the role of dSUR during viral infection in Drosophila and contributed to the writing of the paper. B. Beutler contributed to the mutagenesis effort and to the design of experiments and their written presentation.

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Correspondence to Bruce Beutler.

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Croker, B., Crozat, K., Berger, M. et al. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nat Genet 39, 1453–1460 (2007). https://doi.org/10.1038/ng.2007.25

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