A blood RNA transcript signature for TB exposure in household contacts

Abstract

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.

Keywords: Biomarkers; TB exposure; TB infection; RNA sequencing; Tuberculosis; gene expression; Whole blood.

Fig. 1

Protein-protein network of the 186 exposure genes. Each circle represents a protein encoded by a gene. Colors were assigned proteins that belong to three overrepresented pathways relevant to TB infection. Type 1 interferon signaling pathway (red circles: IFI6, IFITM2, IRF7, ISG15, OASL, RSAD2, XAF1); Inflammatory response (blue circles: CLEC7A, CLU, CXCL1, CXCL5, FFAR2, FPR1, IL1R1, IL1RN, PF4, PF4V1, PLSCR1, PPBP, TNFAIP6, TPST10); Neutrophil mediated immunity (green circles: ANXA3, CEACAM3, CXCL1, CXCL5, CXCR1, FCGR2A, FCGR3B, FOLR3, FPR1, GPR97, PGLYRP1, PPBP, RAP1A, SLPI, TNFAIP6)