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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Bacterial sepsis triggers an antiviral response that causes translation shutdown

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 1

Sepsis causes a biphasic translation derangement.

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Sepsis causes a biphasic translation derangement. (A and B) Time-course ...
(A and B) Time-course analysis of global protein synthesis in a murine model of sepsis (LPS, 5 mg/kg tail vein, i.v.), as determined by incorporation of puromycin to growing polypeptide chains in vivo. Kidneys were harvested 30 minutes after puromycin administration at various time points in the sepsis timeline. Representative Western blot and its quantification are shown. (C) Imaging of nascent protein synthesis in kidney tissues using O-propargyl-puromycin (OPP), an alkyne analog of puromycin, in vivo. Alexa Fluor 555–azide was conjugated to OPP by copper(I)-catalyzed azide-alkyne cycloaddition (Click chemistry). Prox, proximal tubules; dist, distal tubules/collecting ducts. Original magnification, ×60. (D and E) Polysomal profiling of kidney extracts from mice treated with LPS for indicated durations. Cycloheximide was injected at the time of sacrifice to prevent the release of ribosomes from the cognate mRNA. Ribosomal subunit 40S, 60S, mono-ribosome (80S), and polyribosomes were separated using sucrose density gradient. (D) Increased mono-ribosome and poly-ribosome signals indicating increased protein synthesis are observed in the early phases of sepsis (LPS, 1, 2, and 4 hours). (E) Increased mono-ribosome, but decreased poly-ribosome, fractions indicating initiation block and decreased protein synthesis are observed 16 hours after LPS administration. Representative UV absorbance traces from each time point are overlaid, and for comparison, an identical trace (LPS, 4 hours) is shown in both D and E. Polysome-to-monosome ratios: 3.0, 3.5, 4.7, 3.1, 1.9, and 3.7 at 0, 1, 2, 4, 16, and 28 hours, respectively.