The identification of tuberculosis biomarkers in human urine samples

Young, Brandy; Mlamla, Zandile; Gqamana, Putuma P.; Smit, Salome; Roberts, Teri; Peter, Jonny; Theron, Grant; Govender, Ureshnie; Dheda, Keertan; Blackburn, Jonathan M.

doi:10.1183/09031936.00175113

Cited by 62 publications

(52 citation statements)

References 28 publications

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“…In latent TB, Young et al found 6 mycobacterial proteins that were present in urine of HIV uninfected patients which suggests that products other than LAM may be useful for measuring bacterial load over a wide dynamic range, but these require verification in longitudinal studies [46]. …”

Section: Pathogen Based Models and Biomarkersmentioning

confidence: 99%

Assessment of treatment response in tuberculosis

Rockwood

Bruyn

Morris

et al. 2016

Expert Review of Respiratory Medicine

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Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokineticpharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.

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Section: Pathogen Based Models and Biomarkersmentioning

confidence: 99%

Assessment of treatment response in tuberculosis

Rockwood

Bruyn

Morris

et al. 2016

Expert Review of Respiratory Medicine

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“…In this respect, urine has been regarded as the most preferred source of diagnostic biomarkers due to its ease of collection and reduced need for pretreatment compared with other sources. Young et al recently reported the identification of tuberculosis protein biomarkers in human urine samples and concluded that 3 of 10 mycobacterial proteins identified in the urine of TB patients are promising biomarkers for POC diagnostic testing for TB (2). The Campos-Neto group reported a list of TB-diagnostic urine biomarkers (3), among which the Rv1681 protein was clinically validated with sensitivity (44%) for TB diagnosis(4).…”

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confidence: 99%

“…Because urine is a top-priority biomarker source for point-of-care (POC) testing, systematic approaches for identifying tuberculosis antigens in human urine samples have recently been made (2)(3)(4). Lipoarabinomannan (LAM) is one of the best known biomarkers found in urine, and the assay for detecting LAM in the urine of TB patients is commercially available (5)(6)(7).…”

mentioning

confidence: 99%

Identification of Mycobacterial Antigens in Human Urine by Use of Immunoglobulin G Isolated from Sera of Patients with Active Pulmonary Tuberculosis

Kim

Lee

et al. 2016

J Clin Microbiol

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f Point-of-care (POC) diagnostic testing of tuberculosis (TB) is a tremendous unmet need. In this study, four urinary mycobacterial antigens were identified through two independent approaches using IgG capture and immunodepletion methods. Among these, ModC was validated by a multiple reaction monitoring (MRM) method. As expected, the biomarkers elevated the clinical validity of TB diagnosis when combined with preexisting markers. The high morbidity and mortality rates of mycobacterial tuberculosis (TB) necessitate the development of a reliable and convenient diagnostic system with easy accessibility and high diagnostic performance (1). Because urine is a top-priority biomarker source for point-of-care (POC) testing, systematic approaches for identifying tuberculosis antigens in human urine samples have recently been made (2-4). Lipoarabinomannan (LAM) is one of the best known biomarkers found in urine, and the assay for detecting LAM in the urine of TB patients is commercially available (5-7). The LAM tests show a wide range of sensitivity and specificity and have particular clinical utility for the diagnosis of TB in HIV-infected patients (7-9). Recently, the Campos-Neto group reported the identification of TB antigens in urine samples, but the biomarker reportedly fell short of its expected performance. with a diagnostic sensitivity of less than 50% (4).There is still an urgent need to identify more sensitive and specific biomarkers in urine for TB diagnosis. We aimed to identify potential biomarkers in urine through a unique approach whereby IgG was used to capture mycobacterial antigens in urine samples. We thought that patients' IgGs displaying differential binding patterns toward TB antigens could be used to capture the counterpart antigens excreted into the urine. For this, serum samples were collected from patients with active pulmonary tuberculosis, and IgG molecules were purified on a protein G column. The IgG fractions were clearly resolved from those of the rest of the serum proteome, where the purity of IgG molecules in fraction B was Ն 95% as assessed by an electropherogram of stained SDS-PAGE gels (data not shown).To test whether the IgG fractions contained antimycobacterial antibodies, binding patterns were analyzed by Western blotting using the purified IgG as a primary antibody. First, Mycobacterium tuberculosis H37Rv cells were cultured, and all lysates and secretomes were obtained. After heat denaturation, the lysates were separated into buffer-soluble and insoluble fractions and immunoblotted against IgG samples purified from the healthy individuals (Fig. 1A) or the TB patients (Fig. 1B). Representative stained SDS-PAGE gels are shown in Fig. S1A in the supplemental material. The overall pattern was that the IgG samples from the TB patients were more responsive to binding with mycobacterial proteins than those from the healthy individuals. The healthy individuals seemed to possess responsive antibodies, which may be explained by inferring that humans have innately developed a repertoire of a...

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“…Extensive reviews of the translational research progress in the urinary proteomic field have been published [2, 41, 49-51]. Potential urinary biomarkers are being discovered in a variety of non-kidney associated diseases including acute appendicitis [52, 53], infectious diseases such as Tuberculosis [54], Chagas Disease and Lyme Disease [55-57], cancer [49, 50, 58-61], cardiovascular disease [62-64], and aging [65, 66]. Selected examples of the progress in urinary protein identification are described below, highlighting a) improvements in mass spectrometry-based urinary proteomic discovery, b) the number of identifiable proteins, and c) pathophysiologic associations over the last decade.…”

Section: Summary Of Urinary Proteomic Biomarker Discovery To Datementioning

confidence: 99%

Current state of the art for enhancing urine biomarker discovery

Harpole

Davis

Espina

2016

Expert Review of Proteomics

109

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Urine is a highly desirable biospecimen for biomarker analysis because it can be collected recurrently by non-invasive techniques, in relatively large volumes. Urine contains cellular elements, biochemicals, and proteins derived from glomerular filtration of plasma, renal tubule excretion, and urogenital tract secretions that reflect, at a given time point, an individual's metabolic and pathophysiologic state. High-resolution mass spectrometry, coupled with state of the art fractionation systems are revealing the plethora of diagnostic/prognostic proteomic information existing within urinary exosomes, glycoproteins, and proteins. Affinity capture pre-processing techniques such as combinatorial peptide ligand libraries and biomarker harvesting hydrogel nanoparticles are enabling measurement/identification of previously undetectable urinary proteins. Future challenges in the urinary proteomics field include a) defining either single or multiple, universally applicable data normalization methods for comparing results within and between individual patients/data sets, and b) defining expected urinary protein levels in healthy individuals.

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The identification of tuberculosis biomarkers in human urine samples

Cited by 62 publications

References 28 publications

Assessment of treatment response in tuberculosis

Assessment of treatment response in tuberculosis

Identification of Mycobacterial Antigens in Human Urine by Use of Immunoglobulin G Isolated from Sera of Patients with Active Pulmonary Tuberculosis

Current state of the art for enhancing urine biomarker discovery

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