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

Authors :
Chan KR
Gan ES
Chan CYY
Liang C
Low JZH
Zhang SL
Ong EZ
Bhatta A
Wijaya L
Lee YH
Low JG
Ooi EE
Source :
Nature medicine [Nat Med] 2019 Aug; Vol. 25 (8), pp. 1218-1224. Date of Electronic Publication: 2019 Jul 15.
Publication Year :
2019

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 explored <superscript>1-4</superscript> , 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.

Details

Language :
English
ISSN :
1546-170X
Volume :
25
Issue :
8
Database :
MEDLINE
Journal :
Nature medicine
Publication Type :
Academic Journal
Accession number :
31308506
Full Text :
https://doi.org/10.1038/s41591-019-0510-7