Daily Rhythms of TNFα Expression and Food Intake Regulate Synchrony of Plasmodium Stages with the Host Circadian Cycle

Cell Host Microbe. 2018 Jun 13;23(6):796-808.e6. doi: 10.1016/j.chom.2018.04.016. Epub 2018 May 24.


The Plasmodium cell cycle, wherein millions of parasites differentiate and proliferate, occurs in synchrony with the vertebrate host's circadian cycle. The underlying mechanisms are unknown. Here we addressed this question in a mouse model of Plasmodium chabaudi infection. Inflammatory gene expression and carbohydrate metabolism are both enhanced in interferon-γ (IFNγ)-primed leukocytes and liver cells from P. chabaudi-infected mice. Tumor necrosis factor α (TNFα) expression oscillates across the host circadian cycle, and increased TNFα correlates with hypoglycemia and a higher frequency of non-replicative ring forms of trophozoites. Conversely, parasites proliferate and acquire biomass during food intake by the host. Importantly, cyclic hypoglycemia is attenuated and synchronization of P. chabaudi stages is disrupted in IFNγ-/-, TNF receptor-/-, or diabetic mice. Hence, the daily rhythm of systemic TNFα production and host food intake set the pace for Plasmodium synchronization with the host's circadian cycle. This mechanism indicates that Plasmodium parasites take advantage of the host's feeding habits.

Keywords: IFNγ; Plasmodium; TNFα; energy metabolism; food intake; glucose; insulin; malaria and circadian cycle.

Publication types

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

MeSH terms

  • Animals
  • Carbohydrate Metabolism / genetics
  • Cell Cycle / immunology
  • Circadian Rhythm / immunology
  • Circadian Rhythm / physiology*
  • Diabetes Mellitus, Experimental
  • Disease Models, Animal
  • Eating
  • Energy Metabolism
  • Gene Expression Regulation*
  • Glucose / metabolism
  • Host-Parasite Interactions / immunology
  • Host-Parasite Interactions / physiology
  • Hypoglycemia
  • Insulin / metabolism
  • Interferon-gamma / metabolism
  • Leukocytes / metabolism
  • Leukocytes / parasitology
  • Liver / metabolism
  • Liver / parasitology
  • Malaria / immunology
  • Malaria / metabolism*
  • Mice
  • Plasmodium / pathogenicity
  • Plasmodium / physiology*
  • Plasmodium chabaudi / parasitology*
  • Plasmodium chabaudi / pathogenicity
  • Receptors, Tumor Necrosis Factor
  • Trophozoites / physiology
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Insulin
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Glucose