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 language | English (US) |
|---|---|
| Article number | CI123284 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Bacterial sepsis triggers an antiviral response that causes translation shutdown
AU - Hato, Takashi
AU - Maier, Bernhard
AU - Syed, Farooq
AU - Myslinski, Jered
AU - Zollman, Amy
AU - Plotkin, Zoya
AU - Eadon, Michael
AU - Dagher, Pierre
PY - 2019/1/2
Y1 - 2019/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058844653&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058844653&partnerID=8YFLogxK
U2 - 10.1172/JCI123284
DO - 10.1172/JCI123284
M3 - Article
C2 - 30507610
AN - SCOPUS:85058844653
VL - 129
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 1
M1 - CI123284
ER -