Frontiers in Immunology (Sep 2023)

Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis

  • Andy Y. An,
  • Arjun Baghela,
  • Peter Zhang,
  • Reza Falsafi,
  • Amy H. Lee,
  • Uriel Trahtemberg,
  • Uriel Trahtemberg,
  • Andrew J. Baker,
  • Claudia C. dos Santos,
  • Robert E. W. Hancock

DOI
https://doi.org/10.3389/fimmu.2023.1254873
Journal volume & issue
Vol. 14

Abstract

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IntroductionSevere COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features, suggesting that severe COVID-19 is a form of viral sepsis. Our objective was to identify shared gene expression trajectories strongly associated with eventual mortality between severe COVID-19 patients and contemporaneous non-COVID-19 sepsis patients in the intensive care unit (ICU) for potential therapeutic implications.MethodsWhole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Using systems biology methods, drug candidates targeting key genes in the pathophysiology of COVID-19 and sepsis were identified.ResultsWhen compared to survivors, non-survivors (irrespective of COVID-19 status) had 3.6-fold more “persistent” genes (genes that stayed up/downregulated at both timepoints) (4,289 vs. 1,186 genes); these included persistently downregulated genes in T-cell signaling and persistently upregulated genes in select innate immune and metabolic pathways, indicating unresolved immune dysfunction in non-survivors, while resolution of these processes occurred in survivors. These findings of persistence were further confirmed using two publicly available datasets of COVID-19 and sepsis patients. Systems biology methods identified multiple immunomodulatory drug candidates that could target this persistent immune dysfunction, which could be repurposed for possible therapeutic use in both COVID-19 and sepsis.DiscussionTranscriptional evidence of persistent immune dysfunction was associated with 28-day mortality in both COVID-19 and non-COVID-19 septic patients. These findings highlight the opportunity for mitigating common mechanisms of immune dysfunction with immunomodulatory therapies for both diseases.

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