A hub gene signature as a therapeutic target and biomarker for sepsis and geriatric sepsis-induced ARDS concomitant with COVID-19 infection

Front Immunol. 2023 Sep 26:14:1257834. doi: 10.3389/fimmu.2023.1257834. eCollection 2023.

Abstract

Background: COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks.

Methods: We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing sepsis and sepsis-induced ARDS in the context of COVID-19 infection, as well as co-existing or sequentially occurring infections. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS.

Results: Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes.

Conclusion: Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes prospective alternative pathways for targeted therapeutic interventions.

Keywords: COVID-19; bioinformatics; disease biomarker; hub gene; sepsis; sepsis-ARDS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biomarkers
  • COVID-19* / complications
  • COVID-19* / genetics
  • Gene Expression Profiling
  • Humans
  • Mice
  • Respiratory Distress Syndrome* / complications
  • Respiratory Distress Syndrome* / genetics
  • Sepsis* / complications
  • Sepsis* / genetics

Substances

  • Biomarkers

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by contributions from the Guangzhou Science and Technology Plan Projects, China (grant number 2023A04J0595 for GQ), the National Natural Science Foundation of China (grant numbers 81971863 and 82272230 for HF), the Natural Science Foundation of Shanghai, China (grant number 22ZR1444700 for HF), and the Science and Technology Research Project of Song jiang District, China (2017sjkjgg24 for SZ).