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; Andrew J Baker; Claudia C Dos Santos; Robert E W Hancock

doi:10.3389/fimmu.2023.1254873

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

Front Immunol. 2023 Sep 26:14:1254873. doi: 10.3389/fimmu.2023.1254873. eCollection 2023.

Authors

Andy Y An¹, Arjun Baghela¹, Peter Zhang¹, Reza Falsafi¹, Amy H Lee², Uriel Trahtemberg^{3

4}, Andrew J Baker³, Claudia C Dos Santos³, Robert E W Hancock¹

Affiliations

¹ Center for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, BC, Canada.
² Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
³ Keenan Research Center for Biomedical Science and the Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
⁴ Department of Critical Care, Galilee Medical Center, Nahariya, Israel.

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.

Keywords: COVID-19; drug repurposing; gene expression; immune dysfunction; sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
COVID-19*
Humans
Intensive Care Units
Sepsis*
Viremia

Grants and funding

Funding from Canadian Institutes for Health Research (CIHR) FDN-154287 to RH and CIHR COVID-19 Rapid Research Funding to RH and AL is gratefully acknowledged. RH holds a UBC Killam Professorship and held a Canada Research Chair. AA is funded by a Canada Graduate Scholarships Doctoral (CGS-D) program. The COVID-19 Longitudinal Biomarkers of Lung Injury study (COLOBILI) study under which these samples were collected was funded by the St. Michael’s Foundation, an Immune Task Force Grant, and a CIHR grant (GA4-177735) to CS and AJB. CS is supported by the CIHR (MOP-130331, MOP-106545, CIHR/NSERC MOP-510282 2020) and the University of Toronto Robert and Dorothy Pitts Research Chair in Acute Care and Emergency Medicine.