A blood RNA transcript signature for TB exposure in household contacts

Background Current tools for diagnosing latent TB infection (LTBI) detect immunological memory of past exposure but are unable to determine whether exposure is recent. We sought to identify a whole-blood transcriptome signature of recent TB exposure. Methods We studied household contacts of TB patients; healthy volunteers without recent history of TB exposure; and patients with active TB. We performed whole-blood RNA sequencing (in all), an interferon gamma release assay (IGRA; in contacts and healthy controls) and PET/MRI lung scans (in contacts only). We evaluated differentially-expressed genes in household contacts (log2 fold change ≥1 versus healthy controls; false-discovery rate < 0.05); compared these to differentially-expressed genes seen in the active TB group; and assessed the association of a composite gene expression score to independent exposure/treatment/immunological variables. Results There were 186 differentially-expressed genes in household contacts ( n = 26, age 22–66, 46% male) compared with healthy controls ( n = 5, age 29–38, 100% male). Of these genes, 141 (76%) were also differentially expressed in active TB ( n = 14, age 27–69, 71% male). The exposure signature included genes from inflammatory response, type I interferon signalling and neutrophil-mediated immunity pathways; and genes such as BATF2 and SCARF1 known to be associated with incipient TB. The composite gene-expression score was higher in IGRA-positive contacts ( P = 0.04) but not related to time from exposure, isoniazid prophylaxis, or abnormalities on PET/MRI (all P > 0.19). Conclusions Transcriptomics can detect TB exposure and, with further development, may be an approach of value for epidemiological research and targeting public health interventions.