Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis.
Front Immunol
; 14: 1254873, 2023.
Article
em En
| MEDLINE
| ID: mdl-37822940
ABSTRACT
Introduction:
Severe 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.Methods:
Whole 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.Results:
When 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.Discussion:
Transcriptional 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
COVID-19
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
Front Immunol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Canadá