Blood transcriptomics to characterize key biological pathways and identify biomarkers for predicting mortality in melioidosis

Abstract

Melioidosis is a tropical infectious disease caused by the Gram-negative bacillus, Burkholderia pseudomallei that is often lethal in many endemic areas. The objective of this study was to characterize the transcriptome in melioidosis patients and identify genes associated with outcome. RNA-seq was performed on whole blood RNA in a discovery set of 29 melioidosis patients and 3 healthy controls using Ion AmpliSeq Transcriptome. Transcriptomic profiles of patients who did not survive to 28 days were compared with patients who survived and healthy controls. RT-qPCR of 28 differentially expressed genes was performed in a validation set of 60 melioidosis patients and 20 healthy controls. In RNAseq analysis, 65 genes were significantly up-regulated and 218 were down-regulated in nonsurvivors compared to survivors. Up-regulated genes were involved in myeloid leukocyte activation, Toll-like receptor cascades and reactive oxygen species metabolic processes. Down-regulated genes were hematopoietic cell lineage, adaptive immune system and lymphocyte activation pathways. RT-qPCR in the validation set of patients confirmed differential expression of a subset of genes. IL1R2, GAS7, S100A9, IRAK3, and NFKBIA were significantly higher in non-survivors compared with survivors (P < 0.005) and healthy controls (P < 0.0001). The AUROCC of these genes for mortality discrimination ranged from 0.80-0.88. In survivors, expression of IL1R2, S100A9 and IRAK3 genes decreased significantly over 28 days (P < 0.05). Whole blood transcriptomics characterizes the host response in melioidosis. Expression levels of specific genes are potential biomarkers to predict outcomes. These findings augment our understanding of this severe infection.

A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis

“…IRAK3 gene expression was upregulated in blood samples from patients with sepsis, and associated with susceptibility to severe sepsis, poor outcomes and mortality [ 20 , 91 ]. IRAK3 mRNA levels in survivors of sepsis were significantly lower than in non-survivors [ 20 , 92 ], increased within the first five days after diagnosis, and decreased at day 28 when patients recovered [ 92 ]. Thus, the increases of IRAK3 gene expression in patients with sepsis is more extended compared to human in vivo models where IRAK3 mRNA expression increased at ST—IT and declined to baseline at 24h ( Fig 2 ).…”

Effects of exercise on whole‐blood transcriptome profile in children with overweight/obesity

“…IκBα may be regulated by NF‐kB activity (higher in type II patients compared to healthy controls), when NF‐kB activity is increased will increase the expression of IκBα quickly to reduce the activity of NF‐kB (He et al, 2010). Another study showed that NFKBIA gene expression was significantly higher in whole‐blood of non‐survivors melioidosis patients than survivors (Yimthin et al, 2021). Thus, the reduction of NFKBIA gene expression levels could partially indicate a lower pro‐inflammatory profile after exercise intervention in boys.…”

BurkHostGEN: a study protocol for evaluating variations in the Burkholderia pseudomallei and host genomes associated with melioidosis infection

“…Given a SNP and a continuous gene expression data, we used a linear regression 28 to calculate the sample size with different minor allele frequencies (MAF). Using Bonferroni correction for 200,000 hypotheses based on 20,000 genes and an average of 10 SNPs in proximity of each gene as in 29 , we estimated that the size of 600 samples, which is the feasible size collected through this project and compiled with previous reports 30 , 31 , will give 80% power for detecting eQTL with a MAF at 0.03 ( Figure 2b ).…”