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Centre for Tuberculosis

Research Focus

The CTR conducts a spectrum of research focusing on TB infection and disease in humans and animals to provide knowledge and build capacity that informs the development of new diagnostics and treatment regimens. Our key focus areas can be divided into ten main research thrusts, which span from basic to translational research.

The Animal TB Research programme uses a “One Health” approach to investigate interactions and interfaces affecting TB in multi-host ecosystems, working with conservation organisations, veterinarians, epidemiologists, human TB experts, and other professionals. The research projects involve a diverse array of species including rhinoceros, elephant, meerkats, mongooses, lions, warthogs, hyenas and wild dogs.

The programme takes a multi-pronged approach to improving knowledge of the epidemiology, pathogenesis and immunology of members of the Mycobacterium tuberculosis complex (MTBC). This includes

  1. Investigating the role of host, pathogen and environmental factors influencing risk of infection and development of disease
  2. The genetic diversity of mycobacterial pathogens affecting wildlife and domestic animals
  3. Comparative immunological responses, with a focus on the development of diagnostic assays.

Led by the NRF SARChI chair in Animal TB, Prof. Miller, this programme incorporates a continuum of basic to applied research both in the laboratory and field. Research outputs will inform evidence-based management and policies on disease control.

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Our group has a diverse team of fundamental and applied scientists and staff, comprised of post-doctoral fellows, students, technicians and a clinical recruitment team made up of research nurses, community health workers, and drivers. We are led by Prof. Grant Theron.

Our research focuses on three key areas of research into tuberculosis. These include:

  1. the diagnosis of tuberculosis and drug resistance
  2. the study of patient infectiousness and tuberculosis transmission
  3. the microbiome of tuberculosis patients.

Ongoing projects within the group include:

  1. Field evaluations of the new Xpert Ultra, MTBDRsl, and urine LAM tests for pulmonary and extrapulmonary TB
  2. “Hacking” the Xpert cartridge to use it as a tool for DNA extraction for further genotypic drug susceptibility testing
  3. Sampling the cough aerosol of different types of TB patients, and studying the impact of novel drugs and different respiratory manoeuvres on patient infectiousness
  4. Investigating the physiological state and airborne survival of different Mycobacterium tuberculosis clinical isolates
  5. Studying the role of the microbiome in predicting TB treatment response and relapse

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Our research is aimed at understanding the interface between host and pathogen, to gain a better understanding of how the pathogen Mycobacterium tuberculosis interacts with its host to cause disease. Specific research areas include:

  1. advancing our understanding of TB host-pathogen interactions, with a particular focus on persistent mycobacteria,
  2. elucidating the biology PE/PPE proteins of M. tuberculosis
  3. developing new host-directed nanoparticle therapies for TB.

To achieve this, our research exploits molecular mycobacteriology and data-rich omics-based techniques, such as whole genome sequencing, transcriptomics, proteom​ics and cytomics, together with in vitro and in vivo infection models to explore this fundamental aspect of infection biology. These methods are underpinned by computational approaches.

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Our research interrogates three broad research focus areas to expedite discovery of new treatments for tuberculosis on all fronts

  1. Repurposing of existing drugs for the treatment of tuberculosis
  2. Identifying novel targets in M. tuberculosis for the development of direct antituberculosis drugs and
  3. Identifying novel targets in host macrophages to develop host-directed therapeutics.

We employ in-vitro cell culture mycobacterial infection protocols using human macrophages to access small molecule antitubercular drug candidates and how host genes either knocked down or induced affect mycobacterial survival. We employ high-throughput omics such as RNAseq/AmliSeq, Proteomics and Metabolomics.

Current projects aim to develop and test inhibitors that are active against the enzymes of mycothiol/ergothioneine and Nitrogen metabolism pathways in Mycobacterium tuberculosis as possible new antitubercular drugs. We are also investigating the gene expression and proteomic changes in macrophages infected with pathogenic and non-pathogenic mycobacterial strains, in search of host factors that influence survival of mycobacteria in macrophages.

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The Immunology Research Group is​ a multi-disciplinary academic team of scientists, doctors, nurses, laboratory personnel and students​, led by Prof Gerhard Walzl. 

Our research comprises several focus areas, each investigating a different immunological aspect of TB disease. These include:

  1. Immune biomarkers discovery for novel diagnostics, treatment monitoring, protective immunity, and new treatment regimens, as well as vaccines development.
  2. Innate Immunity, particularly the role of regulatory myeloid cells, and how these cells prevent us from launching optimal protection against Mtb
  3. Adaptive Immunity, with a particular focus on regulatory B-cells and their immunogenic products to determine how these cells influence TB disease onset and progression.
  4. Immune-endocrine interactions and particularly the role of Type 2 Diabetes Mellitus in TB susceptibility.

Our team works in conjunction with several international consortia with several US, European and African partners, as well as the Biomedical Research Institute Clinical Unit on large cohorts for clinical trial operations involving volunteer study participants. Our laboratory team processes a range of sample types from participants, including serum, urine, saliva, sputum, exhaled breath condensate, broncho-alveolar lavage, pleural fluid and cerebrospinal fluid.

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As tuberculosis research in South Africa has become increasingly reliant on molecular biotechnologies, the volume of data produced has grown considerably. The South African Tuberculosis Bioinformatics Initiative (SATBBI) was founded in response to this growth, creating a group of bioinformatics researchers engaged with the tuberculosis research community in South Africa.

Modern molecular experiments using massively parallel techniques produce tremendous volumes of data. The sheer volume can obscure valuable information. The bioinformatics team maximizes the information yield from these experiments, this included:

  1. Core experiment design, statistical evaluation, and machine learning approaches, with special applications in high-throughput sequencing.
  2. design and statistical analysis of complex studies.

SATBBI is also the driving force behind the Research Commons Data (ResComDat) project, an initiative to implement a large capacity storage system based on Ceph technology. The ResComDat project will provide infrastructure that can expand to exabyte capacity and is intended to be a repository for large data sets, from high-throughput techniques, such as next-generation sequencing, mass spectrometry and CyTOF, with well-annotated data (FAIR compliant).

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Our group focuses on comparative genomics by whole genome sequencing (WGS), transcriptomics using RNA-seq, and proteomics, allowing us to investigate the epidemiology and evolution of Mycobacterium tuberculosis.

We are currently building a genome sequence bank, comprising thousands of sequences of local clinical isolates – complementing our vast sample bank. These sequences allow us to scrutinize the local epidemic in terms of outbreak investigations, within-patient evolution of drug-resistance, transmission and discovering novel drug-resistance causing mutations. By combining WGS with RNA-seq or proteomics we are able to determine the impact of drug resistance on the physiology of Mycobacterium tuberculosis.

We are also involved in the development and evaluation of rapid molecular diagnostics for the detection of drug resistance that are based on information generated through molecular epidemiology studies/data, helping to tailor diagnostics to the local epidemic.

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Our research aims to answer one very important question ‘Why do some people get TB and others not?’ Most infected people never develop the disease, and our focus is on the genetic underpinnings of this inter-individual variation.

The immune response genes play a major role and our research aims to identify the unknown host genes controlling resistance. We use our very large sample bank and databank together with sequencing technologies, state-of-the-art genotyping and bioinformatics analysis methods to find genes influencing susceptibility to TB and primary immunodeficiencies in a South African population with a very high incidence. We also take the work to the cellular level by studying the functional pathways of the genes discovered.

Our research team also study genetic diversity in sub-Saharan Africa to further assist research in populations of African descent, which will be important in selecting appropriate and efficacious TB vaccines for these populations.

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Bioprospecting and discovery of novel bioactive entities biosynthesized by fungi associated with medicinal plants, marine sponges and gold mine tailings/dumps. The objective is the utilization of these secondary metabolites for the development of anti-TB drug leads. This approach combines the benefits provided by marine microbial bioactive agents with desirable chemical synthetic scaffolds to generate pseudo-natural products with enhanced bioactive properties and modes of action.

The aims of our research group are to:

  1. Identify novel antimycobacterial bioactive agents including bacteriocins from microbial symbionts associated with marine sponges.
  2. Develop marine invertebrate cell culture models to generate more novel bioactive agents.
  3. Semi-synthesise pseudo-natural products.
  4. Investigate the utility of our preparations in treating various Mycobacterial tuberculosis-infected cell lines (liver, heart, kidney and astrocytes).

Our collaborations are multidisciplinary and include nanochemistry, organometallic chemistry, marine biologists and computational chemistry experts.

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