Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103147 | GEO | 2017/10/17

SECONDARY ACCESSION(S): PRJNA400331

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:The aim of the project was to define transcriptional signatures in whole blood of TB patients (before drug treatment) and healthy controls to distinguish the signature of Latent and Active TB patients from each other and from healthy controls. This will help in diagnosis of active tuberculosis which normally relies on culture of the bacilli, which can take up to 6 wks, and sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques obtaining bronchoalveolar lavage (BAL). In some cases the bacill cannot be grown from sputum or BAL. Secondly the aim was to determine whether Latent patients have a homogeneous or heterogeneous signature, one may expect the latter since it is not possible to determine by the present tests (Tuberculin skin test - TST - or MTb antigen responsiveness of blood cells to produce IFN-gamma - IGRA assay) whether the mycobacteria has been cleared, is still present but is controlled, or if patients are recently infected or reactivated and will develop active TB. The latter situation may be determined if Latent patients have a blood transcriptional signature similar to that in Active patients. The transcriptional signature in Active TB patients may also provide information as to the factors leading to immunopathogenesis, thus possibly identifying therapeutic targets. The transcriptional profile in Latent TB may give information as to the protective factors controlling the infection, thus important for monitoring vaccine development. A further aim was to examine the transcriptional blood profile of active TB patients at the time of recruitment (before drug treatment) and then subsequently at specific time points after drug treatment to determine whether the signature is extingsuihed with treatment and when. London is a site of intermediate burden of TB - the study was initiated in London, across a broad range of ethnicities to obtain a robust signature that could be used in different developing countries where there is a high burden TB disease. Experimental design : Whole blood collected in tempus tubes from patients with different spectra of TB disease and healthy controls. All patients were sampled prior to the initiation of any antimycobacterial therapy. Active Pulmonary TB: PTB - All patients confirmed by isolation of Mycobacterium Tuberculosis on culture of sputum or bronchoalvelolar lavage fluid. Latent TB: LTB - All patients were screened at a tuberculosis clinic, being either new entrants to the UK from endemic countries or being household contacts of infectious cases. All were positive by tuberculin skin test (>14mm if BCG vaccinated, >5mm if not vaccinated) and were also positive by Interferon-Gamma Release assay(IGRA); specifically Quantiferon Gold In-Tube Assay (Cellestis, Australia). Latent patients had no clinical, radiological or microbiological evidence of active infection and were asymptomatic. Healthy controls - these were volunteers without exposure to TB who were negative by both tuberculin skin test (<15mm if BCG vaccinated, <6mm if unvaccinated); who were also negative by IGRA (as described above). In this dataset: PTB n= 13; LTB n = 17; BCG+ n = 6, BCG-, n =6. Experimental variables : Patient group: Active PTB; Latent TB, Healthy controls (BCG vaccinated and unvaccinated). ethnicity - a wide range of ethnic groups is represented. However all controls in this dataset are broadly Caucasian/White. The active PTB group incorporates a range of smear positive and smear negative disease and a spectrum of disease extent/severity.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure