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

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

Chan KR1, Gan ES2,3, Chan CYY2,4, Liang C5, Low JZH6, Zhang SL2, Ong EZ3, Bhatta A2, Wijaya L4, Lee YH5,7, Low JG8,9,10,11, Ooi EE12,13,14,15.

Author information

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.

PMID:
31308506
DOI:
10.1038/s41591-019-0510-7

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