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Introduction
Skills and Expertise
Publications
Publications (116)
Background
Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood transcriptomic TB signatures for differentiating between symptomatic patients who have TB versus other respiratory diseases (ORD).
Methods
As part of a nested cas...
Background
There is an urgent need for biomarkers that predict TB treatment response in clinical practice and research. Despite its poor specificity and sensitivity, sputum microscopy and culture conversion 8 weeks following treatment initiation remains the recommended surrogate for TB treatment response. A blood-based biomarker with the ability to...
Background:
To improve tuberculosis (TB) diagnosis, the World Health Organisation (WHO) has called for a non-sputum based triage test to focus TB testing on people with a high likelihood of having active pulmonary tuberculosis (TB). Various host or pathogen biomarker-based testing devices are in design stage and require validity assessment. Host b...
Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two lon...
Researchers would generally adjust for the possible confounding effect of population structure by considering global ancestry proportions or top principle components. Alternatively, researchers would conduct admixture mapping to increase the power to detect variants with an ancestry effect. This is sufficient in simple admixture scenarios, however,...
Background
Recombination maps are important resources for epidemiological and evolutionary analyses; however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We infer the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derive a nov...
Mass cytometry is one of the most popular single-cell technology that can measure over 50 markers simultaneously for millions of cells. Due to the high-dimensional nature of the dataset, manual analysis is difficult. Furthermore, during biological sample preparation, some problems may arise that need to be dealt with. One of the problems is a batch...
Background
Natural immunity against Mycobacterium tuberculosis exists, and > 90% of those infected remain disease-free. Innate and adaptive immune responses required to mediate such protection against tuberculosis (TB) are, however, poorly understood.
Methods
This is an analytical study exploring protective and non-protective pathways of immunity...
Myeloid-derived suppressor cells (MDSC) have been identified in the peripheral blood and granulomas of patients with active TB disease, but their phenotype-, function-, and immunosuppressive mechanism- spectrum remains unclear. Importantly, the frequency and signaling pathways of MDSC at the site of disease is unknown with no indication how this co...
Background
Antibodies against mycobacterial proteins are highly specific, but lack sensitivity, whereas cytokines have been shown to be sensitive but not very specific in the diagnosis of tuberculosis (TB). We assessed combinations between antibodies and cytokines for diagnosing TB.
Methods
Immuoglubulin (Ig) A and IgM antibody titres against sele...
Researchers would generally adjust for the possible confounding effect of population structure by considering global ancestry proportions or top principle components. Alternatively, researchers would conduct admixture mapping to increase the power to detect variants with an ancestry effect. This is sufficient in simple admixture scenarios, however,...
Recombination maps are important resources for epidemiological and evolutionary analyses, however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We inferred the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derived a novel, pop...
Background:
The development of a fast and accurate, non-sputum-based point-of-care triage test for tuberculosis (TB) would have a major impact on combating the TB burden worldwide. A new fingerstick blood test has been developed by Cepheid (the Xpert-MTB-Host Response (HR)-Prototype), which generates a 'TB score' based on mRNA expression of 3 gene...
To date, numerous software tools have been developed to infer recombination maps. Many of these software tools infer the recombination rate from linkage disequilibrium, and therefore they infer recombination many generations into the past. Other recently developed methods rely on the inference of recent recombination events to determine the recombi...
Despite decades of research and advancements in diagnostics and treatment, tuberculosis remains a major public health concern. New computational methods are needed to interrogate the intersection of host- and bacterial genomes. Paired host genotype datum and infecting bacterial isolate information were analysed for associations using a multinomial...
The development of a non-sputum-based, point-of-care diagnostic test for tuberculosis (TB) is a priority in the global effort to combat this disease, particularly in resource-constrained settings. Previous studies have identified host biomarker signatures which showed potential, but there is a need to validate and refine these for development as a...
Background: We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulate...
Background: Recent interferon gamma (IFN-c)-based studies have identified novel Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens as diagnostic candidates. In this study, the levels of 11 host markers other than IFN-c, were evaluated in whole blood culture supernatants after stimulation with M.tb infection phase-dependent antigen...
Objective
To investigate the potential of host urinary biomarkers as diagnostic candidates for TB.
Methods
Adults self-presenting with symptoms requiring further investigation for TB were enrolled in Cape Town, South Africa. Participants were later classified as having TB or other respiratory diseases (ORD) using results from TB confirmatory tests...
Despite decades of research and advancements in diagnostics and treatment, tuberculosis remains a major public health concern, particularly in low and middle income countries. New bioinformatics and computational methods are needed to interrogate the intersection of host and bacterial genomes and identify novel targets for anti tuberculosis drugs....
Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tu...
Biosignatures for TB diagnosis in Sub-saharan Africa
The South African Medical Research Council Centre for Tuberculosis Research has a rich history of high-impact research that has
influenced our understating of this hyper-epidemic which is further exacerbated by the emergence and spread of drug-resistant forms of the
disease. This review aims to summarise the past 30 years of research conducted in t...
Biomarkers for TB treatment response and outcome are needed. This study characterize changes in immune profiles during TB treatment, define biosignatures associated with treatment outcomes, and explore the feasibility of predictive models for relapse. Seventy-two markers were measured by multiplex cytokine array in serum samples from 78 cured, 12 r...
Background
Inexpensive rapid screening tests that can be used at the point-of-care (POC) are vital to combat tuberculosis. Particularly, less invasive non-sputum-based biomarker tests for all TB forms can help controlling transmission. Availability of such tests would significantly accelerate and streamline diagnostic approaches, improve cost-effic...
There remains a pressing need for biomarkers that can predict who will progress to active tuberculosis (TB) after exposure to Mycobacterium tuberculosis (MTB) bacterium. By analyzing cohorts of household contacts of TB index cases (HHCs) and a stringent non-human primate (NHP) challenge model, we evaluated whether integration of blood transcription...
Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB)-exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of...
Rationale:
Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.
Objectives:
We investigated biosignatures with predictive ability for incident tuberculosis.
Methods:
In a case-control study nes...
We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomar...
We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomar...
A bidirectional communication between the immune and endocrine systems exists and facilitates optimum responses in the host during infections. This is in part achieved through changes in secretion patterns of hypothalamic hormones induced by inflammatory cytokines. The aim of this study was to elucidate the immune–endocrine alterations during tuber...
Background:
Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Bacille Calmette-Guérin (BCG) vaccine, previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target populati...
Background:
There is an urgent need for new tools for the early diagnosis of TB disease and monitoring of the response to treatment, especially in resource-constrained settings. We investigated the usefulness of host markers detected in saliva as candidate biomarkers for the immunological diagnosis of TB disease and monitoring of treatment respons...
Background User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Afri...
Background:
There is an urgent need for new tools for the rapid diagnosis of tuberculosis (TB) disease in resource-constrained settings. Tests based on host immunological biomarkers maybe useful, especially if based on easily available samples. We investigated host biomarkers detected in saliva samples from individuals with suspected pulmonary TB...
Elevated rates of reinfection tuberculosis in various hyperendemic regions have been reported and, in particular, it has been shown that in a high-incidence setting near Cape Town, South Africa, the rate of reinfection tuberculosis (TB) disease after cure of a previous TB disease episode is about four times greater than the rate of first-time TB di...
There is an urgent need for new tools for the rapid diagnosis of tuberculosis disease. We evaluated the potentials of 74 host markers as biomarkers for the immunological diagnosis of tuberculosis and monitoring of treatment response. Fiftyfive individuals that presented with signs and symptoms requiring investigation for tuberculosis disease were p...
Background
We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated...
Background:
There is increasing evidence from tuberculosis high-burden settings that exogenous reinfection contributes considerably to recurrent disease. However, large longitudinal studies of endogenous reactivation (relapse) and reinfection tuberculosis are lacking. We hypothesize a relationship between relapse vs reinfection and the time betwee...
Background:
The development of active tuberculosis disease has been shown to be multifactorial. Interactions between host and bacterial genotype may influence disease outcome, with some studies indicating the adaptation of M. tuberculosis strains to specific human populations. Here we investigate the role of the human leukocyte antigen (HLA) class...
The diagnosis of tuberculosis remains challenging in individuals with difficulty in providing good quality sputum samples such as children. Host biosignatures of inflammatory markers may be valuable in such cases, especially if they are based on more easily obtainable samples such as saliva. To explore the potential of saliva as an alternative samp...
Background
Recent interferon gamma (IFN-γ)-based studies have identified novel Mycobacterium tuberculosis (M.tb) infection phase-dependent antigens as diagnostic candidates. In this study, the levels of 11 host markers other than IFN-γ, were evaluated in whole blood culture supernatants after stimulation with M.tb infection phase-dependent antigen...
Median levels of all analytes evaluated (pg/ml) and ranges (in parentheses) elicited upon stimulation of whole blood cells with different M. tuberculosis infection phase-dependent antigens and abilities to discriminate between pulmonary TB disease (in 15 cases) and no TB (in 15 household contacts). AUC, area under the curve; 95% CI = 95% confidence...
The relative contributions of transmission and reactivation of latent infection to TB cases observed clinically has been reported in many situations, but always with some uncertainty. Genotyped data from TB organisms obtained from patients have been used as the basis for heuristic distinctions between circulating (clustered strains) and reactivated...
This file describes the origin and consequences of the inherent instability in estimating the vector A with equation (4).
(DOC)
This file provides the algorithm for creating hypothetical populations for a given sample and code to reproduce the results in Table 1.
(DOC)
This file describes the derivation of Equations (1)–(3).
(DOC)
Genotyping of multidrug-resistant (MDR) Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in four South African provinces (Western Cape, Eastern Cape, KwaZulu-Natal,
and Gauteng) revealed a distinct population structure of the MDR strains in all four regions, despite the evidence of substantial
human migration between thes...
Brewelskloof Hospital, Western Cape, South Africa.
To verify the perceived increase in rifampicin monoresistant tuberculosis (RMR-TB) in the Cape Winelands-Overberg region and to identify potential risk factors.
A retrospective descriptive study of trends in RMR-TB over a 5-year period (2004-2008), followed by a case-control study of RMR and isonia...
To determine the nutritional status of children attending a cystic fibrosis clinic in a tertiary hospital in South Africa and compare it to previously reported 10-year rates.
Weights and heights were measured of 69 (37 male and 32 female) children aged between 1 year and 18 years. Expected weight-for-age, expected height-for-age, expected weight-fo...
Temporal analysis of drug-resistant tuberculosis (TB) cases in the Western Cape, South Africa, showed a 1.5-fold increase over a 2-year period, suggesting a doubling time of 8.2 years. This increase was strongly associated with multidrug resistance and the Beijing genotype. Forty-two per cent of the overall increase was due to the Beijing genotype...
Current anti-tuberculosis (anti-TB) drug sensitivity testing methods provide a dichotomous readout: isolates are reported as either drug susceptible or drug resistant. This report demonstrates that rapid molecular methods may provide information concerning both the level of resistance and cross-resistance to other anti-TB drugs that is important fo...
Mycobacterium tuberculosis strains can be classified into a number of major clades according to defined evolutionary markers. It is hypothesised that strains comprising these clades have evolved different properties which may influence a local strain population structure. To investigate this, we analysed the incidence of tuberculosis caused by the...
Many molecular epidemiological investigations of M. tuberculosis are reported using data collected over relatively short timeframes. We postulated that such studies would tend to under-estimate the amount of disease in a community attributable to ongoing transmission. To test this hypothesis we used 12-year datasets of both real and simulated epide...
IS6110 restriction fragment length polymorphism (RFLP) genotyping is the most widely used genotyping method to study the epidemiology of Mycobacterium tuberculosis. However, due to the complexity of the IS6110 RFLP genotyping technique, and the interpretation of RFLP data, mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MI...
The emergence and transmission of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB)
have raised concern about diagnostic delay associated with culture-based drug susceptibility testing methods. The association
between rifampin resistance and MDR-TB or XDR-TB makes it an important genetic marker for genot...