Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance

Cell. 2019 Apr 4;177(2):399-413.e12. doi: 10.1016/j.cell.2019.01.050. Epub 2019 Mar 7.


Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.

Keywords: caloric restriction; dormancy; hibernation; innate immunity; ketones; metabolism; resistance; thermoneutrality; torpor; triglycerides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature Regulation / immunology*
  • Body Temperature Regulation / physiology
  • Energy Metabolism / immunology
  • Energy Metabolism / physiology
  • Female
  • Immune Tolerance / immunology
  • Immune Tolerance / physiology
  • Immunity / physiology*
  • Immunity, Innate / physiology*
  • Male
  • Metabolism / immunology
  • Mice
  • Mice, Inbred C57BL