Editors' ChoiceInfection

Feast and famine, sickness and health

Sci. Signal.  20 Sep 2016:
Vol. 9, Issue 446, pp. ec217
DOI: 10.1126/scisignal.aaj2244

Loss of appetite and lack of interest in food are common symptoms of infectious disease. Wang et al. explored how glucose availability affected the immune response to and outcome of viral and bacterial infections in mice. Glucose supplementation of mice during infection with the bacterium Listeria monocytogenes increased mortality, whereas glucose supplementation during infection with influenza virus enhanced survival. In both infections, mortality appeared to result from neurological damage, resulting in seizures during bacterial infection and dysregulation of heart rate and body temperature in viral infection. To investigate these effects independently of the effect that host glucose metabolism has on the pathogen itself, mice were exposed to lipopolysaccharide, a bacterial molecule recognized by Toll-like receptor 4 (TLR4), or poly(I:C), a synthetic analog of viral RNA that is recognized by TLR3. LPS and poly(I:C) challenges were carried out with or without glucose supplementation and in the presence or absence of 2-deoxy-D-glucose (2DG), which competes with glucose for hexokinase in the glycolysis pathway and thus blocks glucose metabolism. Glucose supplementation or 2DG treatment during the LPS challenge did not affect plasma concentration of the proinflammatory cytokines tumor necrosis factor–α or interleukin-6 and during poly (I:C) challenge did not affect the plasma concentration of the antiviral cytokine interferon-α. Ketogenesis appeared to be important in survival of bacterial but not viral infection, with ketogenesis-deficient (Ppara–/– and Fgf21–/–) mice dying in response to LPS but surviving influenza. Ketogenesis commonly occurs during fasting, when fatty acids and amino acids are the primary compounds used for cellular metabolism and may result in a cellular metabolic state that can protect the brain from the cytotoxic effects of reactive oxygen species, which are produced in response to bacterial infection. The protective effect of glucose in the mice exposed to poly(I:C) depended on the transcription factor CHOP, which is involved in the adaptive response to endoplasmic reticulum stress. Thus, glucose metabolism interacted with different pathways potentially protective against inflammation-induced damage depending on the infectious agent. Mounting an appropriate immune response is an energy-requiring process. Undoubtedly, glucose availability and metabolism also affect the adaptive immune response and the function of monocytes. However, this study suggests that the effects of glucose availability on cells’ ability to tolerate inflammatory signals vary with different types of infection, which could have critical implications for patient care, especially for diabetic patients, if this difference is conserved in humans. Ayres discusses the implications of these findings for understanding the evolution of defenses against disease.

A. Wang, S. C. Huen, H. H. Luan, S. Yu, C. Zhang, J.-D. Gallezot, C. J. Booth, R. Medzhitov, Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 (2016). [PubMed]

J. S. Ayres, Disease tolerance trick or treat: Give your brain something good to eat. Cell 166, 1368–1370 (2016). [PubMed]

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