High-resolution quantitative proteomics applied to the study of the specific protein signature in the sputum and saliva of active tuberculosis patients and their infected and uninfected contacts

Mateos, Jesús; Estévez, Olivia; González-Fernández, África; Anibarro, Luis; Pallarés, Ángeles; Reljić, Rajko; Gallardo, José Manuel; Medina, Isabel; Carrera, Mónica

doi:10.1016/j.jprot.2019.01.010

Cited by 27 publications

(20 citation statements)

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“…Biomarker discovery in biological fluids using high-resolution proteomics allows researchers to identify the modulation of cellular pathways when comparing different disease progression states. In the previous work, we focused on the analysis of nasal/oral fluid samples to obtain a deeper understanding of the innate immune processes implicated in resistance to the initial MTB infection 27 . In the present study, by analyzing serum samples of active TB patients and their contacts, our aim was to focus on the mechanisms activated systematically in the host during the progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Uninfected contacts remained free of MTB infection despite high degree exposure to an active TB patient (Table 1). We have recently identified some components of the innate immune response that specifically accumulate in the sputum of these uninfected individuals when compared with LTBI contacts 27 , indicating the importance of nasal/oral secretions as a first barrier to fighting the initial entry of MTB. In the present study, using the same approach, we were unable to detect any serum protein significantly accumulated in uninfected contacts versus LTBI contacts (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4). All these proteins were previously identified as accumulated in serum samples of TB patients with antibody-based techniques 37,38 , by label-free mass spectrometry 36 , and more recently in saliva and sputum samples 27 . To the best of our knowledge, other proteins, such as neutrophil defensin 1 and lysozyme C, have not been previously described as being accumulated in the serum of active TB patients.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were selected for the quantitative proteomics study according to their protein concentration and integrity. Labelling and fractionation of the protein samples were done as previously described 27 . Briefly, 100 µg of each individual sample was resuspended in a final volume of 100 µL of 0.1 M TEAB buffer solution, reduced/alkylated and digested with trypsin for 16 h at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

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

Mateos

Estévez

González-Fernández

et al. 2020

Sci Rep

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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 .

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Mateos

Estévez

González-Fernández

et al. 2020

Sci Rep

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“…Previous studies carried out in our research group (13)(14)(15)(16)(17) identi ed putative protein biomarkers for the diagnosis of TB, or as tools for monitoring the response to treatment. Furthermore, a recent study by Mateos and colleagues (18) identi ed protein signatures in saliva and sputum that distinguished active TB patients from their infected and uninfected contacts using labelled quanti cation. However, most of these studies were Luminex technology-based, and depended largely on targeted approaches relying on the presence of capture and detection antibodies or speci c protein tags to measure each protein.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel salivary candidate protein biomarkers for tuberculosis diagnosis

Mutavhatsindi

Calder

McAnda

et al. 2020

Preprint

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Background: The diagnosis of TB remains one of the major challenges in the control of the disease, due to limitations in the currently available diagnostic tests. There is an urgent need for new, accurate, rapid, and affordable diagnostic tests. The aim of the present study was to use mass spectrometry to identify new candidate TB diagnostic protein biomarkers in saliva obtained from individuals with TB, and patients with other respiratory diseases (ORD).Methods: Saliva samples were collected from 22 individuals who self-presented with symptoms requiring investigation for TB as part of a larger TB biomarker project. Eleven of the participants were finally diagnosed with TB using routine clinical, radiological and laboratory tests and 11 with ORD. Salivary proteins were concentrated and purified, followed by tryptic digestion. Peptides were analyzed using a QExactive Orbitrap MS coupled to a Dionex liquid chromatography system. Raw files were processed using MaxQuant software against the database of human proteins. Identified proteins were subjected to gene ontology and ingenuity pathway analysis for functional enrichment analysis.Results: We identified 1176 protein groups across all samples, of which 46 (3.91%) were contaminants, 12 (1.02%) were reverse hits and 170 (14.46%) were single-peptide protein groups. After removal of the contaminants, reverse hits and protein groups represented by single peptides, 26 of the remaining 948 proteins significantly discriminated individuals with TB from those with ORD after Benjamini Hochberg correction, with five of these proteins diagnosing TB with AUC ³ 0.80. A 5-protein biosignature comprising of P01011, Q8NCW5, P28072, A0A2Q2TTZ9 and Q99574 diagnosed TB with an AUC of 1.00 (95% CI, 1.00-1.00), sensitivity of 100% (95% CI, 76.2-100%) and specificity of 90.9% (95% CI, 58.7-99.8%) after leave-one-out cross validation. Conclusions: We identified novel salivary protein biomarkers and biosignatures with strong potential as TB diagnostic candidates. Our results are preliminary and require validation in larger studies.

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From simple to complex: Protein‐based biomarker discovery in tuberculosis

Mousavian,

Källenius,

Sundling

2023

Eur J Immunol

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Tuberculosis (TB) is a deadly infectious disease that affects millions of people globally. TB proteomics signature discovery has been a rapidly growing area of research that aims to identify protein biomarkers for the early detection, diagnosis, and treatment monitoring of TB. In this review, we have highlighted recent advances in this field and how it is moving from the study of single proteins to high‐throughput profiling and from only using proteomics to include additional types of data in multi‐omics studies. We have further covered the different sample types and experimental technologies used in TB proteomics signature discovery, focusing on studies of HIV‐negative adults. The published signatures were defined as either coming from hypothesis‐based protein targeting or from unbiased discovery approaches. The methodological approaches influenced the type of proteins identified and were associated with the circulating protein abundance. However, both approaches largely identified proteins involved in similar biological pathways, including acute‐phase responses and T‐helper type 1 and type 17 responses. By analysing the frequency of proteins in the different signatures, we could also highlight potential robust biomarker candidates. Finally, we discuss the potential value of integration of multi‐omics data and the importance of control cohorts and signature validation.This article is protected by copyright. All rights reserved

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High-resolution quantitative proteomics applied to the study of the specific protein signature in the sputum and saliva of active tuberculosis patients and their infected and uninfected contacts

Cited by 27 publications

References 55 publications

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

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

Identification of novel salivary candidate protein biomarkers for tuberculosis diagnosis

From simple to complex: Protein‐based biomarker discovery in tuberculosis

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