Differential Metabolic Reprogramming by Zika Virus Promotes Cell Death in Human versus Mosquito Cells

Shivani K Thaker; Travis Chapa; Gustavo Garcia Jr; Danyang Gong; Ernst W Schmid; Vaithilingaraja Arumugaswami; Ren Sun; Heather R Christofk

doi:10.1016/j.cmet.2019.01.024

Differential Metabolic Reprogramming by Zika Virus Promotes Cell Death in Human versus Mosquito Cells

Cell Metab. 2019 May 7;29(5):1206-1216.e4. doi: 10.1016/j.cmet.2019.01.024. Epub 2019 Feb 28.

Authors

Shivani K Thaker¹, Travis Chapa², Gustavo Garcia Jr², Danyang Gong², Ernst W Schmid³, Vaithilingaraja Arumugaswami⁴, Ren Sun⁵, Heather R Christofk⁶

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90098, USA.
⁵ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: rsun@mednet.ucla.edu.
⁶ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: hchristofk@mednet.ucla.edu.

Abstract

Zika virus is a pathogen that poses serious consequences, including congenital microcephaly. Although many viruses reprogram host cell metabolism, whether Zika virus alters cellular metabolism and the functional consequences of Zika-induced metabolic changes remain unknown. Here, we show that Zika virus infection differentially reprograms glucose metabolism in human versus C6/36 mosquito cells by increasing glucose use in the tricarboxylic acid cycle in human cells versus increasing glucose use in the pentose phosphate pathway in mosquito cells. Infection of human cells selectively depletes nucleotide triphosphate levels, leading to elevated AMP/ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and caspase-mediated cell death. AMPK is also phosphorylated in Zika virus-infected mouse brain. Inhibiting AMPK in human cells decreases Zika virus-mediated cell death, whereas activating AMPK in mosquito cells promotes Zika virus-mediated cell death. These findings suggest that the differential metabolic reprogramming during Zika virus infection of human versus mosquito cells determines whether cell death occurs.

Keywords: AMPK; Zika virus; apoptosis; virus metabolism.

Publication types

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

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors
AMP-Activated Protein Kinases / metabolism
Aedes / cytology*
Animals
Cell Death*
Chlorocebus aethiops
Citric Acid Cycle
Epithelial Cells / metabolism*
Epithelial Cells / microbiology*
Fibroblasts / metabolism*
Fibroblasts / microbiology*
Foreskin / cytology
Glucose / metabolism
Humans
Male
Mice
Mice, Knockout
Pentose Phosphate Pathway
Phosphorylation
Receptor, Interferon alpha-beta / genetics
Retinal Pigment Epithelium / cytology
Vero Cells
Zika Virus / metabolism*
Zika Virus Infection / metabolism*
Zika Virus Infection / virology

Substances

Ifnar1 protein, mouse
Receptor, Interferon alpha-beta
AMP-Activated Protein Kinases
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding