Phagocytosis by hemocytes, Drosophila macrophages, is essential for resistance to Streptococcus pneumoniae in adult flies. Activated macrophages require an increased supply of energy and we show here that a systemic metabolic switch, involving the release of glucose from glycogen, is required for effective resistance to S. pneumoniae. This metabolic switch is mediated by extracellular adenosine, as evidenced by the fact that blocking adenosine signaling in the adoR mutant suppresses the systemic metabolic switch and decreases resistance to infection, while enhancing adenosine effects by lowering adenosine deaminase ADGF-A increases resistance to S. pneumoniae. Further, that ADGF-A is later expressed by immune cells during infection to regulate these effects of adenosine on the systemic metabolism and immune response. Such regulation proved to be important during chronic infection caused by Listeria monocytogenes. Lowering ADGF-A specifically in immune cells prolonged the systemic metabolic effects, leading to lower glycogen stores, and increased the intracellular load of L. monocytogenes, possibly by feeding the bacteria. An adenosine-mediated systemic metabolic switch is thus essential for effective resistance but must be regulated by ADGF-A expression from immune cells to prevent the loss of energy reserves and possibly to avoid the exploitation of energy by the pathogen.

Department of Molecular Biology and Genetics Faculty of Science University of South Bohemia in Ceske Budejovice Ceske Budejovice Czech Republic

See more in PubMed

Palsson-McDermott EM, O’Neill LAJ. The Warburg effect then and now: From cancer to inflammatory diseases: Review essays. BioEssays. 2013;35: 965–973. doi: 10.1002/bies.201300084 PubMed DOI

Spies CM, Straub RH, Buttgereit F. Energy metabolism and rheumatic diseases: from cell to organism. Arthritis Res Ther. 2012;14: 216–216. doi: 10.1186/ar3885 PubMed DOI PMC

Gerriets VA, MacIver NJ. Role of T cells in malnutrition and obesity. Inflammation. 2014;5: 379 doi: 10.3389/fimmu.2014.00379 PubMed DOI PMC

Passalacqua KD, Charbonneau M-E, O’Riordan MXD. Bacterial metabolism shapes the host:pathogen interface. Microbiol Spectr. 2016;4 doi: 10.1128/microbiolspec.VMBF-0027-2015 PubMed DOI PMC

Ayres JS, Schneider DS. The role of anorexia in resistance and tolerance to infections in Drosophila. PLoS Biol. 2009;7: e1000150–e1000150. doi: 10.1371/journal.pbio.1000150 PubMed DOI PMC

Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot J-D, et al. Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation. Cell. 2016;166: 1512–1525.e12. doi: 10.1016/j.cell.2016.07.026 PubMed DOI PMC

Dionne MS, Pham LN, Shirasu-Hiza M, Schneider DS. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr Biol. 2006;16: 1977–1985. doi: 10.1016/j.cub.2006.08.052 PubMed DOI

Straub RH. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther. 2014;16: S4 doi: 10.1186/ar4688 PubMed DOI PMC

Straub RH, Schradin C. Chronic inflammatory systemic diseases—an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol Med Public Health. 2016; eow001 doi: 10.1093/emph/eow001 PubMed DOI PMC

Eisenreich W, Heesemann J, Rudel T, Goebel W. Metabolic host responses to infection by intracellular bacterial pathogens. Front Cell Infect Microbiol. 2013;3 doi: 10.3389/fcimb.2013.00024 PubMed DOI PMC

Bajgar A, Kucerova K, Jonatova L, Tomcala A, Schneedorferova I, Okrouhlik J, et al. Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response. PLoS Biol. 2015;13: e1002135 doi: 10.1371/journal.pbio.1002135 PubMed DOI PMC

Antonioli L, Csóka B, Fornai M, Colucci R, Kókai E, Blandizzi C, et al. Adenosine and inflammation: what’s new on the horizon? Drug Discov Today. 2014;19: 1051–1068. doi: 10.1016/j.drudis.2014.02.010 PubMed DOI

Davis JM, Zhao Z, Stock HS, Mehl KA, Buggy J, Hand GA. Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol—Regul Integr Comp Physiol. 2003;284: R399–R404. doi: 10.1152/ajpregu.00386.2002 PubMed DOI

Collis MG. The vasodilator role of adenosine. Pharmacol Ther. 1989;41: 143–162. doi: 10.1016/0163-7258(89)90104-6 PubMed DOI

Shimkets LJ, Dworkin M. Excreted adenosine is a cell density signal for the initiation of fruiting body formation in Myxococcus xanthus. Dev Biol. 1981;84: 51–60. doi: 10.1016/0012-1606(81)90369-9 PubMed DOI

Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS. A Specific Primed Immune Response in Drosophila Is Dependent on Phagocytes. PLOS Pathog. 2007;3: e26 doi: 10.1371/journal.ppat.0030026 PubMed DOI PMC

Dolezal T, Dolezelova E, Zurovec M, Bryant PJ. A role for adenosine deaminase in Drosophila larval development. PLoS Biol. 2005;3: e201 doi: 10.1371/journal.pbio.0030201 PubMed DOI PMC

Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Dev Camb Engl. 1993;118: 401–415. PubMed

Louie A, Song KH, Hotson A, Tate AT, Schneider DS. How Many Parameters Does It Take to Describe Disease Tolerance? PLOS Biol. 2016;14: e1002435 doi: 10.1371/journal.pbio.1002435 PubMed DOI PMC

Chambers MC, Lightfield KL, Schneider DS. How the fly balances its ability to combat different pathogens. PLoS Pathog. 2012;8: e1002970–e1002970. doi: 10.1371/journal.ppat.1002970 PubMed DOI PMC

Mansfield BE, Dionne MS, Schneider DS, Freitag NE. Exploration of host-pathogen interactions using Listeria monocytogenes and Drosophila melanogaster. Cell Microbiol. 2003;5: 901–911. doi: 10.1046/j.1462-5822.2003.00329.x PubMed DOI

Ayres JS, Schneider DS. A Signaling Protease Required for Melanization in Drosophila Affects Resistance and Tolerance of Infections. PLOS Biol. 2008;6: e305 doi: 10.1371/journal.pbio.0060305 PubMed DOI PMC

Dolezal T, Gazi M, Zurovec M, Bryant PJ. Genetic analysis of the ADGF multigene family by homologous recombination and gene conversion in Drosophila. Genetics. 2003;165: 653–66. PubMed PMC

Straub RH. Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J Mol Med. 2012;90: 523–534. doi: 10.1007/s00109-012-0861-8 PubMed DOI PMC

Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25: 771–784. doi: 10.1038/cr.2015.68 PubMed DOI PMC

Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature. 2013;501: 512–516. doi: 10.1038/nature12566 PubMed DOI PMC

Chico-Calero I, Suárez M, González-Zorn B, Scortti M, Slaghuis J, Goebel W, et al. Hpt, a bacterial homolog of the microsomal glucose-6-phosphate translocase, mediates rapid intracellular proliferation in Listeria. Proc Natl Acad Sci. 2002;99: 431–436. doi: 10.1073/pnas.012363899 PubMed DOI PMC

Portnoy DA. A 20-year perspective on Listeria monocytogenes pathogenesis Listeria monocytogenes: Pathogenesis and Host Response. Springer; 2007. pp. 1–12. http://link.springer.com/chapter/10.1007/978-0-387-49376-3_1 DOI

Novakova M, Dolezal T. Expression of Drosophila adenosine deaminase in immune cells during inflammatory response. PloS One. 2011;6: e17741 doi: 10.1371/journal.pone.0017741 PubMed DOI PMC

Joyce EA, Kawale A, Censini S, Kim CC, Covacci A, Falkow S. LuxS Is Required for Persistent Pneumococcal Carriage and Expression of Virulence and Biosynthesis Genes. Infect Immun. 2004;72: 2964–2975. doi: 10.1128/IAI.72.5.2964-2975.2004 PubMed DOI PMC

Tennessen JM, Barry W, Cox J, Thummel CS. Methods for studying metabolism in Drosophila. Methods. 2014;68: 105–115. doi: 10.1016/j.ymeth.2014.02.034 PubMed DOI PMC

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