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

Kuan Rong Chan1, Esther Shuyi Gan2,3, Candice Yuen Yue Chan2,4, Cui Liang5, John Zhong Heng Low6, Summer Li-Xin Zhang2, Eugenia Ziying Ong3, Ashwin Bhatta2, Limin Wijaya4, Yie Hou Lee5,7, Jenny Guek-Hong Low8,9,10,11, Eng Eong Ooi12,13,14,15

  1. Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore. kuanrong.chan@duke-nus.edu.sg.
  2. Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore.
  3. Viral Research & Experimental Medicine Center, SingHealth/Duke-NUS (ViREMiCS), Singapore, Singapore.
  4. Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
  5. Singapore-MIT Alliance in Research and Technology, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore.
  6. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  7. KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore.
  8. Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore. jenny.low@singhealth.com.sg.
  9. Viral Research & Experimental Medicine Center, SingHealth/Duke-NUS (ViREMiCS), Singapore, Singapore. jenny.low@singhealth.com.sg.
  10. Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore. jenny.low@singhealth.com.sg.
  11. Singapore-MIT Alliance in Research and Technology, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore. jenny.low@singhealth.com.sg.
  12. Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.
  13. Viral Research & Experimental Medicine Center, SingHealth/Duke-NUS (ViREMiCS), Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.
  14. Singapore-MIT Alliance in Research and Technology, Antimicrobial Resistance Interdisciplinary Research Group, Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.
  15. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. engeong.ooi@duke-nus.edu.sg.

Abstract

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.

Presented by Kuan Rong Chan

Medicine, Genetics & Genome BiologyVictoria Fang2019-08 (Aug)