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

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 RNA-seq analysis, 65 genes were significantly up-regulated and 218 were down-regulated in non-survivors 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.