Serum proteomics of active tuberculosis patients and contacts reveals unique processes activated during Mycobacterium tuberculosis infection

Abstract

Tuberculosis (TB) is the most lethal infection among infectious diseases. The specific aim of this study was to establish panels of serum protein biomarkers representative of active tB patients and their household contacts who were either infected (LtBi) or uninfected (eMi-tB Discovery cohort, Pontevedra Region, Spain). A TMT (Tamdem mass tags) 10plex-based quantitative proteomics study was performed in quintuplicate containing a total of 15 individual serum samples per group. Peptides were analyzed in an Lc-orbitrap elite platform, and raw data were processed using proteome Discoverer 2.1. A total of 418 proteins were quantified. The specific protein signature of active tB patients was characterized by an accumulation of proteins related to complement activation, inflammation and modulation of immune response and also by a decrease of a small subset of proteins, including apolipoprotein A and serotransferrin, indicating the importance of lipid transport and iron assimilation in the progression of the disease. This signature was verified by the targeted measurement of selected candidates in a second cohort (EMI-TB Verification Cohort, Maputo Region, Mozambique) by ELISA and nephelometry techniques. These findings will aid our understanding of the complex metabolic processes associated with tB progression from LtBi to active disease. Tuberculosis (TB) is currently a global pandemic that kills approximately 1.3 million people worldwide each year 1. Although the incidence of TB is decreasing each year, the rate of that decline is not high enough to accomplish the TB Global Strategy for the 2015-2035 period 2,3. Mycobacterium tuberculosis (MTB) is the causal agent of the pulmonary TB 4 , which is air-transmitted by nasal/oral inhalation of aerosol droplets carrying the pathogen from an active TB patient to a healthy individual usually through coughing or sneezing 5. Small droplets that are able to reach the lower lung induce formation of a granuloma 6 , which is a host-defensive structure providing, a fibrotic physical barrier between the infected and the healthy neighboring tissues 7. Latently infected individuals (LTBI) represent roughly a quarter of the global population 8. Tuberculin Skin Test (TST) and Interferon-Gamma Release Assay (IGRA) are commonly used for diagnosis 9,10 of LTBI individuals. Although they cannot infect a healthy person, MTB activation occurs in roughly 10% of cases due to recurrent infections or a compromised immune system in the host 11 .

Differences in plasma proteomes for active tuberculosis, latent tuberculosis and non-tuberculosis mycobacterial lung disease patients with and without ESAT-6/CFP10 stimulation

“…Though the excellence of IGRA ELISA to differentiate NTM and TB infection in non-endemic countries was reported [ 70 ], 34–49% IGRA ELISA positive cases were reported in NTM in endemic countries [ 71 ]; this supports our hypothesis that the similarity of protein changes observed for both LTBI and NTM cases are explained by frequent coexistence of LTBI and NTM infection in our study community. The proteins of NTM that were identified in this study and previously described by Jusus et al [ 72 ] appear to reflect cross-reactivity observed between MTBC and NTM exposition. Two proteins such as the charged multivesicular body protein 4a (CHMP4A) and the platelet factor (PF)-4, were up-regulated in NTM as compared to HC and down-regulated in NTM as compared to active TB in this study.…”

Proteomic profiling of biomarkers by MALDI‑TOF mass spectrometry for the diagnosis of tracheobronchial stenosis after tracheobronchial tuberculosis

“…Serum APOAI levels were negatively correlated with the onset of cerebral infarction in patients with carotid artery stenosis ( 43 ). Of note, a recent study demonstrated that APOAI, -AⅡ and -AⅣ were decreased in patients with active TB ( 44 ). Furthermore, rifampicin treatment led to an increase in the level of APOAI in patients with TB; however, there was no statistical significance ( 45 ).…”

Perspectives for systems biology in the management of tuberculosis

“…Sputum proteomics identified a five-protein signature differentiating between tuberculosis and nontuberculosis patients (sensitivity 70%, specificity 79%) [84]. Differential regulation of pro-inflammatory, lipid and iron transport proteins were revealed between patients with active tuberculosis and LTBI patients [74]. A serum three-protein signature distinguished MDR from drug-susceptible tuberculosis (sensitivity 81.2%, specificity 90%) and healthy controls (sensitivity 94.7%, specificity 80%) [85].…”