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Bacterial sepsis triggers an antiviral response that causes translation shutdown
Takashi Hato, … , Michael T. Eadon, Pierre C. Dagher
Takashi Hato, … , Michael T. Eadon, Pierre C. Dagher
Published December 3, 2018
Citation Information: J Clin Invest. 2019;129(1):296-309. https://doi.org/10.1172/JCI123284.
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Research Article Inflammation Nephrology

Bacterial sepsis triggers an antiviral response that causes translation shutdown

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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.

Authors

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

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Figure 6

Translation shutdown mediated by the Eif2ak2/Eif2α axis contributes to sepsis-induced kidney injury.

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Translation shutdown mediated by the Eif2ak2/Eif2α axis contributes to s...
(A) Mice were treated with 5 mg/kg LPS i.v. for indicated durations, and kidneys were analyzed by Western blot for Eif2ak2, Eif2α, and Ser51 p-Eif2α (arrow). (B) Select protein levels as determined by nascent proteomics are shown. (C and D) In vivo effects of ISRIB (5 mg/kg i.p.) on protein synthesis (puromycin incorporation in the kidney; ISRIB for 16 hours) and tissue expression of Eif2ak2, Eif2α, and p-Eif2α (kidneys harvested 16 hours after 5 mg/kg LPS i.v. with or without ISRIB i.p. for 16 hours). LPS increased Eif2ak2 and p-Eif2α. This increase was not affected by ISRIB. (E) Serum creatinine levels 24 hours after LPS with or without ISRIB treatment administered at indicated time points. *P < 0.05 vs. LPS without ISRIB treatment by Student’s t test (2 sided, nonpaired). Error bars show SD.

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