Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation.
Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so-called sickness behaviors are the most common and familiar symptoms of infections, their roles in host defense are largely unknown. Here, we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, whereas blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states. VIDEO ABSTRACT.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Rheumatology), Yale University School of Medicine, New Haven, CT 06520, USA.
Andrew
A
Wang
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Medicine (Nephrology), Yale University School of Medicine, New Haven, CT 06520, USA.
Sarah C
SC
Huen
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Harding H
HH
Luan
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Shuang
S
Yu
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cuiling
C
Zhang
Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520, USA.
Jean-Dominique
JD
Gallezot
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Carmen J
CJ
Booth
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: ruslan.medzhitov@yale.edu.
Ruslan
R
Medzhitov
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000627:therapeutic use; D019468:Disease Management; D005215:Fasting; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D055809:Illness Behavior / Q000502:physiology*; D007249:Inflammation; D007251:Influenza, Human / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008070:Lipopolysaccharides; D008088:Listeriosis / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018529:Nutritional Support / Q000009:adverse effects*; D011070:Poly I-C; D018805:Sepsis / Q000139:chemically induced / Q000517:prevention & control; D051742:Transcription Factor CHOP / Q000378:metabolism
D000963:Antimetabolites; D008070:Lipopolysaccharides; D051742:Transcription Factor CHOP; D003847:Deoxyglucose; D005947:Glucose; D011070:Poly I-C