Dataset Information

Mycobacterium tuberculosis fingerprint in human lungs

ABSTRACT: Tuberculosis (TB) is one of the top ten causes of death worldwide and the leading cause of death from a single infectious agent. Globally, an estimated of 10 million people developed TB in 2018 according to WHO report. An estimated one third of all TB cases are not diagnosed or notified, partly due to the major limitations of current diagnostic tools. To achieve the goals of the WHO’s End TB Strategy, which targets for 2030 a 90% reduction in the number of TB deaths and an 80% reduction in the TB incidence rate compared with levels in 2015, diagnostic tools are critically important. Among the three diagnostic priorities identified by the WHO and the TB community is the development of a point-of-care biomarker-based non-sputum-based test to diagnose pulmonary TB, and ideally also extrapulmonary TB. To be successfully implemented at point-of-cares, a new test should use an easily accessible sample, such as urine, blood or breath condensate. Here, we explored whether bacilli-derived molecules released in the extracellular milieu during infection could be detected in the exhaled breath condensate, allowing a specific diagnosis of TB. Interestingly, we detected by proteomic analysis a set of Mycobacterium tuberculosis proteins in all smear-positive and smear-negative adult patients, as well as of children with TB

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human) Mycobacterium Tuberculosis Mycobacterium Tuberculosis H37rv

SUBMITTER: Alexandre STELLA

LAB HEAD: Jerome Nigou

PROVIDER: PXD028477 | Pride | 2023-03-10

REPOSITORIES: pride

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A Mycobacterium tuberculosis fingerprint in human breath allows tuberculosis detection.

Mosquera-Restrepo Sergio Fabián SF Zuberogoïtia Sophie S Gouxette Lucie L Layre Emilie E Gilleron Martine M Stella Alexandre A Rengel David D Burlet-Schiltz Odile O Caro Ana Cecilia AC Garcia Luis F LF Segura César C Peláez Jaramillo Carlos Alberto CA Rojas Mauricio M Nigou Jérôme J

Nature communications 20221214 1

An estimated one-third of tuberculosis (TB) cases go undiagnosed or unreported. Sputum samples, widely used for TB diagnosis, are inefficient at detecting infection in children and paucibacillary patients. Indeed, developing point-of-care biomarker-based diagnostics that are not sputum-based is a major priority for the WHO. Here, in a proof-of-concept study, we tested whether pulmonary TB can be detected by analyzing patient exhaled breath condensate (EBC) samples. We find that the presence of M ...[more]

PMID: 36517492

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Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. Serum samples collected from adult patients with suspected tuberculosis during a multi-site study was used to probe whole proteome microarrays. Subject recruitment was conducted under uniform protocols approved by the institutional ethics committee at each site. Final diagnosis of active TB was based on positive M. tuberculosis culture results. The active TB patients were further subdivided into smear-positive and negative disease based on results of Ziehl-Neelsen staining of sputum smears for acid fast bacilli. Active TB was excluded as a diagnosis (Non-TB Disease [NTBD] patients) based on having negative M. tuberculosis culture and smear results and on having an alternate diagnosis. All subjects were presumably negative for HIV infection given the very low incidence of HIV infection in the study sites. Sera from 169 TB and 242 NTBD patients were selected for microarray probing. The control sera (n = 14) which was used to generate negative control distribution for each protein were negative to latent M. tuberculosis infection, as indicated by negative results to tuberculin skin test.

Project description:Tuberculosis (TB) still represents a major global health problem affecting over 10 million people worldwide. At present, there is an urgent need for defining prognostic parameters, differential diagnostic, and correlates of protection from the disease. The gold standard test for TB diagnosis is still smear microscopy, but insufficiently detects pulmonary disease, besides the necessity of having laboratory infrastructures and be time-consuming. Both LAM urine test and Xpert MTB/RIF have been major game changers in this context. However, the low sensitivity of the former and the considerable delay of sample delivery of the latter, make the improvement of the TB diagnostic landscape a priority. The development of rapid point-of-care (POC)-based testing approaches would represent an important breakthrough in TB diagnostics in view of these short-comings. Most forms of life produce extracellular vesicles (EVs) and since the first detection of bacterial EVs more than 60 years, subsequent studies have demonstrated their functional commonality despite differences in bacterial cell envelope architecture. We demonstrated that Mycobacterium tuberculosis (Mtb), the causative agent of TB, produces EVs in vitro and in vivo as part of a sophisticated mechanism to manipulate host cellular physiology and to evade the host immune system. In a previous serology study, Mtb EVs (MEVs) were used to investigate their potential role as biomarkers to discern between different forms of disease status. It was shown that the recognition of several MEV associated proteins could have diagnostic properties. In this study, we pursued to expand the capabilities of MEVs in the context of TB diagnostics by analyzing the composition of MEVs isolated from Mtb cultures submitted to iron starvation and, testing their immunogenicity against a new cohort of serum samples including TB+, LTBI and healthy donors. We found that MEVs differ in protein composition when Mtb is under host-related stress yet MEVs seem to carry antigens that could serve as bonafide markers for direct detection. In addition, TB serology revealed three new MEV antigens with great biomarker capacity. These results encourage investigating the feasibility of the development of a POC device based on selected MEV-associated proteins.

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.

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