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

Abstract

BackgroundCOVID-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.MethodsWe 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.ResultsOur 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.ConclusionOur 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.

Differential DNA methylation associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review

“…They have potential clinical utility as a biomarker in early diagnosis or prognosis of DCI and may be targets for therapeutic intervention due to their influential role in gene regulation pathways. Similar utility has been studied in a variety of pathologies such as glioblastoma [ 27 ], sepsis [ 28 ], colorectal cancer [ 29 ], and others [ 30 ].…”

The shared circulating diagnostic biomarkers and molecular mechanisms of systemic lupus erythematosus and inflammatory bowel disease

“…Previous studies have demonstrated that KLRB1 expression is downregulated in SLE ( 51 – 53 ), which is also consistent with the results of this paper. Apart from SLE, aberrant KLRB1 expression has been correlated with other autoimmune diseases and inflammatory responses, including rheumatoid arthritis (RA) ( 54 , 55 ), multiple sclerosis (MS) ( 56 ), and sepsis ( 57 ). Nevertheless, the expression of KLRB1 is not entirely consistent in these immunoinflammatory diseases.…”

“…Nevertheless, the expression of KLRB1 is not entirely consistent in these immunoinflammatory diseases. KLRB1 expression is up-regulated in early RA ( 54 ) and MS ( 56 ) and down-regulated in advanced RA ( 55 ) and sepsis ( 57 ). The exact mechanism remains unclear, but KLRB1 may develop into a biological marker specific to autoimmune diseases in the future.…”