Identification and Validation of Potential miRNAs, as Biomarkers for Sepsis and Associated Lung Injury: A Network-Based Approach.

Shaniya Ahmad,Romana Ishrat,Kailash Manda,Archana Sharma,Mansoor Ali Syed,P M Z Hasan,Anwar L Bilgrami,Mohd Murshad Ahmed

doi:10.3390/genes11111327

Abstract

Sepsis is a dysregulated immune response disease affecting millions worldwide. Delayed diagnosis, poor prognosis, and disease heterogeneity make its treatment ineffective. miRNAs are imposingly involved in personalized medicine such as therapeutics, due to their high sensitivity and accuracy. Our study aimed to reveal the biomarkers that may be involved in the dysregulated immune response in sepsis and lung injury using a computational approach and in vivo validation studies. A sepsis miRNA Gene Expression Omnibus (GEO) dataset based on the former analysis of blood samples was used to identify differentially expressed miRNAs (DEMs) and associated hub genes. Sepsis-associated genes from the Comparative Toxicogenomics Database (CTD) that overlapped with identified DEM targets were utilized for network construction. In total, 317 genes were found to be regulated by 10 DEMs (three upregulated, namely miR-4634, miR-4638-5p, and miR-4769-5p, and seven downregulated, namely miR-4299, miR-451a, miR181a-2-3p, miR-16-5p, miR-5704, miR-144-3p, and miR-1290). Overall hub genes (HIP1, GJC1, MDM4, IL6R, and ERC1) and for miR-16-5p (SYNRG, TNRC6B, and LAMTOR3) were identified based on centrality measures (degree, betweenness, and closeness). In vivo validation of miRNAs in lung tissue showed significantly downregulated expression of miR-16-5p corroborating with our computational findings, whereas expression of miR-181a-2-3p and miR-451a were found to be upregulated in contrast to the computational approach. In conclusion, the differential expression pattern of miRNAs and hub genes reported in this study may help to unravel many unexplored regulatory pathways, leading to the identification of critical molecular targets for increased prognosis, diagnosis, and drug efficacy in sepsis and associated organ injuries.

Highlights

IntroductionSepsis is a complex clinical syndrome triggered by the aberrant host response to an infection [1]
Sepsis is a complex clinical syndrome triggered by the aberrant host response to an infection [1].It is explicitly lethal as it leads to respiratory failure and death [2,3]
The dataset contains 2079 miRNAs in total, of which 862 differentially expressed miRNAs (DEMs) were identified based on two criteria, i.e., fold change > 1.5 and p-value < 0.05

Summary

Introduction

Sepsis is a complex clinical syndrome triggered by the aberrant host response to an infection [1]. It is explicitly lethal as it leads to respiratory failure and death [2,3]. Disease heterogeneity, genetic variability, and poor understanding of sepsis pathophysiology are the significant causes of poor prognosis. It has become a hidden public health disaster over the past decade [7], and the need for prompt diagnosis and stratification of patient’s accuracy is no less essential [8]

Objectives

Methods

Results

Discussion

Conclusion