Sepsis can cause multiple organ failure and is associated with high patient mortality, but how is sepsis linked to widespread organ damage? Takashi Hato, Pierre Dagher and colleagues now report that bacterial sepsis triggers a cellular antiviral response in the kidney; the effects of this response on protein translation potentially lead to organ failure.

The researchers injected lipopolysaccharide (LPS) into mice to induce moderate endotoxaemia, which resulted in severe acute kidney injury. Proximal tubule cells respond to LPS via Toll-like receptor 4 (TLR4) and the researchers used ribosome profiling to establish the ribosome footprint of septic kidneys and assess changes in the kidney translatome over time.

LPS injection induced rapid and transient nuclear factor-κB (NF-κB) activation, which led to a rise in pro-inflammatory cytokines, such as IL-1 and IL-6, in the early stages of sepsis (that is, 4 hours after LPS challenge). Moreover, interferon and interferon-induced antiviral genes were upregulated at this stage and their translation was sustained for up to 28 hours. In contrast to this early increase in protein levels, in late sepsis (that is, 16 hours after LPS challenge) the researchers observed a global decline in protein synthesis. “Protein translation shutdown was preceded by the upregulation of double-stranded RNA-activated protein kinase (Eif2ak2),” adds Hato. In response to viral infections, Eif2ak2 upregulation blocks protein translation in an attempt to prevent viral replication. These effects on translation might directly lead to organ failure, as restoring protein translation was renoprotective in this model.

EIF2AK2 expression was also increased in kidney biopsy samples from patients with acute tubular necrosis related to bacterial sepsis. “Our examination of tissues from patients with sepsis supports a model in humans that is similar to what is observed in mice, although the timescale is potentially different,” explains Dagher.

“Our work links inflammation in the early stages of sepsis to late-stage organ failure at the molecular level,” concludes Dagher.