Bacterial sepsis triggers an antiviral response that causes translation shutdown

Takashi Hato, Bernhard Maier, Farooq Syed, Jered Myslinski, Amy Zollman, Zoya Plotkin, Michael Eadon, Pierre Dagher

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses, as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the eukaryotic translation initiation factor 2-α kinase 2/ eukaryotic translation initiation factor 2α (Eif2ak2/Eif2α) axis is the key mediator of translation initiation block in late-phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings imply that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.

Original languageEnglish (US)
Article numberCI123284
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

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Antiviral Agents
Sepsis
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
Kidney
Wounds and Injuries
Protein Biosynthesis
Genes
Phosphotransferases
Up-Regulation
Viruses

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bacterial sepsis triggers an antiviral response that causes translation shutdown. / Hato, Takashi; Maier, Bernhard; Syed, Farooq; Myslinski, Jered; Zollman, Amy; Plotkin, Zoya; Eadon, Michael; Dagher, Pierre.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI123284, 02.01.2019.

Research output: Contribution to journalArticle

Hato, Takashi ; Maier, Bernhard ; Syed, Farooq ; Myslinski, Jered ; Zollman, Amy ; Plotkin, Zoya ; Eadon, Michael ; Dagher, Pierre. / Bacterial sepsis triggers an antiviral response that causes translation shutdown. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
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