Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease

To define mechanisms that underlie progression of Mycobacterium tuberculosis (M.tb) infection to active tuberculosis (TB), we followed M.tb-infected adolescents longitudinally. Those who ultimately developed TB disease (“progressors”) were compared with matched controls, who remained healthy. Whole blood transcriptomic and plasma proteome analyses showed sequential modulation of immunological processes: type I/II interferon signalling and complement cascade were elevated 18 months before TB diagnosis, while changes in myeloid inflammation and lymphoid cell, monocyte and neutrophil gene modules occurred more proximally to TB disease. Analysis of gene expression in purified T cells revealed early suppression of Th17 responses in progressors. This was confirmed in an adult BCG re-vaccination cohort, where expression of interferon response genes in blood was associated with suppression of IL-17 expression by BCG-specific CD4 cells. We concluded that sequential inflammatory dynamics and immune alteration precede TB disease manifestation, with important implications for developing diagnostics, vaccines and host-directed therapies for TB. 6,363 healthy adolescents, aged 12-18 years and enrolled into the Adolescent Cohort Study (ACS) (Zak et al. 2016), were followed for 24 months or more. Blood was collected at 6-monthly intervals. Among those with evidence of M.tbinfection (QuantiFERON and/or tuberculin skin test positive), 41 ultimately developed microbiologically confirmed TB disease >6 months after study enrolment; they were designated “progressors”. Among progressors, the time from blood collection to diagnosis of active TB (“time to diagnosis”) ranged from 1 to 894 days. Realigning blood collection to “time to diagnosis” allowed serial assessment of transition from infection to TB disease. Controls (N=104), who remained asymptomatic, were matched to progressors by age, gender, ethnicity, school and prior history of TB .