Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live-attenuated yellow fever infection

Nat Med. 2019 Aug;25(8):1218-1224. doi: 10.1038/s41591-019-0510-7. Epub 2019 Jul 15.


Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Citric Acid Cycle
  • Disease Susceptibility
  • Endoplasmic Reticulum Stress*
  • Humans
  • Middle Aged
  • Reactive Oxygen Species / metabolism
  • Vaccines, Attenuated / immunology
  • Yellow Fever / etiology
  • Yellow Fever / metabolism*
  • Yellow Fever Vaccine / immunology*


  • Reactive Oxygen Species
  • Vaccines, Attenuated
  • Yellow Fever Vaccine