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

Frontiers in Immunology

Immunology

Peter Zhang¹  Andy Y. An¹  Reza Falsafi¹  Robert E. W. Hancock¹  Arjun Baghela¹  Amy H. Lee²  Andrew J. Baker³  Claudia C. dos Santos³  Uriel Trahtemberg⁴ 

[1] Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada;Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada;Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada;Department of Critical Care, Galilee Medical Center, Nahariya, Israel;

关键词: COVID-19;    sepsis;    immune dysfunction;    gene expression;    drug repurposing;   

DOI  :  10.3389/fimmu.2023.1254873

 received in 2023-07-07, accepted in 2023-09-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 An, Baghela, Zhang, Falsafi, Lee, Trahtemberg, Baker, Santos and Hancock