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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 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 implicate that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122274 | GEO | 2018/11/16

REPOSITORIES: GEO

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Project description:Background: The role of viral infections as a mediator of systemic immune dysfunction leading to sepsis has received limited attention compared to the bacterial pathogens. The COVID-19 pandemic and the increased cases of sepsis in the absence of known bacterial pathogens have highlighted the clinical relevance of viruses as causative agents of sepsis. In this study, we investigated clinical, laboratory, proteomic, and metabolic characteristics to shed light on the molecular mechanisms underlying the pathological conditions of viral sepsis in COVID-19. Methods: We retrospectively analyzed data from 231 hospitalized patients with confirmed COVID-19 admitted to three hospitals in China. The presence of viral sepsis was diagnosed with SOFA score 2 in the absence of bacterial infection. Demographics, clinical, and laboratory parameters, as well as clinical outcomes, were obtained from electronic chart reviews. Plasma samples were obtained from a subset of these patients (23 patients in the Viral Non-Sepsis [VNS] group and 14 patients in the Viral Sepsis [VS] group) to analyze proteomic and metabolic profiles. Findings: The viral sepsis group exhibited severe disease, as indicated by elevated markers of both pulmonary (ARDS) and systemic disease (liver, kidney, and cardiac injury). Consistent with known immune paralysis observed in sepsis, subjects with viral sepsis were more susceptible to secondary infections by bacterial and fungal pathogens. Overall, viral sepsis led to an increased length of ICU stay, required invasive mechanical ventilation and a significant increase in mortality compared to the non-viral sepsis group. At the molecular levels, we identified unique metabolic and proteomic signatures that suggest a substantial contribution of the coagulation and platelet dysfunction pathways to systemic pathologies. Interpretation: Viral sepsis presents an underrecognized threat contributing to high mortality. Specific metabolic and proteomic changes demonstrated coagulation and platelet dysfunction as key pathological pathway in viral sepsis.

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Bacterial sepsis triggers an antiviral response that causes translation shutdown

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