Molecular Biology Human Genetics
Welcome to Stellenbosch University

Division of Molecular Biology and Human Genetics

​Research

We currently occupy a position bridging the gap between basic research and its application in clinical TB research and management. This laboratory is engaged in fundamental research towards a better understanding of the biology of the bacterium, which enables it to avoid destruction in the host and spread rapidly within human populations. This may result in the identification and characterisation of novel drug targets. It is also at the cutting edge of research to identify novel bacterial and host markers that will considerably shorten the time taken to evaluate new drug and vaccines and to develop new diagnostic tools and new, multidisciplinary approaches for understanding the epidemiology of the disease. Each one of these efforts is aimed at bridging the gap between fundamental research and its clinical application and some have broader application beyond the field of human TB, most notably in areas such as wildlife management and veterinary disease.

 

 

 

 

 

 

 

DIRECTOR: Prof Paul van Helden (pvh@sun.ac.za)  

Molecular Epidemiology

 

 Prof Rob Warren (rw1@sun.ac.za)

M. tuberculosis strains from patients from over 10 different settings in South Africa are genetically characterized using techniques based on the transposition element, IS6110, and other probes. These genotypic data, together with clinical data, are used to study the dynamics of the epidemic. From this database it has been possible to quantify the extent of ongoing transmission, introduce a new paradigm on the mechanism of recurrent disease, demonstrate the importance of exogenous reinfection in producing mixed infections, describe the bacterial population structure in different settings, and predict phylogenetic relationships among epidemic strains. A member of the dominant strain family F11 has been sequenced and in vitro and in vivo studies are being conducted to determine pathogenic mechanisms of this and other strains. Knowledge gained from comparative genomics is being used to develop new diagnostics and speciation methods.

 Drug Resistance

 

Prof Tommie Victor (tv@sun.ac.za)

​Drug resistant TB, especially MDR- and XDR-TB , poses a threat to the success of TB control programmes and places an enormous financial burden on the health budget. Prof Tommie Victor and his team aimed at understanding the epidemiology and evolution of drug resistance. A longitudinal reference drug resistance Database and a large collection of well characterised viable resistant culture bank is maintained and this is central to these investigations. The culture bank, linked to the database, is a national asset which provide many opportunities for research, training, to attract funding, set up collaborations and to guide the national TB program on the control of drug resistant TB. State of art molecular technologies are used to study the evolution of drug resistance and to understand how the bacterium behave under stress conditions by first and second line drugs. This is important, as understanding of these mechanisms will aid in the development of designer drugs and ultimately to control the acquisition and spread of drug resistant TB.

Evolution and Pathogenesis


Prof Nico Gey van Pittius (ngvp@sun.ac.za)

​The genus Mycobacterium consists of around 120 species, many of which, such as M. tuberculosis (the causitive agent of tuberculosis) and M. leprae (the causative agent of leprosy), have evolved to become human and animal pathogens.  Our research focuses on the evolution of the mycobacteria and of mycobacterial pathogenicity and drug resistance.  We are interested in uncovering the mechanisms and targets of these changes, using a combination of tools including mycobacterial molecular biology and genetics, comparative mycobacterial genomics, proteomics, transcriptomics, bioinformatics, phylogenetics and evolutionary analyses. A large part of our work concerns an in-depth investigation of the immunopathologically important ESAT-6 secretion system and its associated genes, which has been shown to be directly involved in the virulence of the mycobacteria.  Our work further extends to the identification of targets which could be applied in tuberculosis diagnosis and anti-tuberculosis drug and vaccine design. 

 Drug Targets and Drug Testing

 
Prof Ian Wiid (iw@sun.ac.za)

​We focus on genes critical to the survival of M.tuberculosis and which are unique to confer specificity as drug targets. We seek to understand their regulation and biology and assist chemists in the design and testing of novel inhibitors. Our main areas of interest are Oxidative stress and nitrogen assimilatory pathways in M.tucerculosis.

Immunology

 
 Prof Gerhard Walzl (gwalzl@sun.ac.za)

​The diagnosis of active tuberculosis (TB) is hampered by the poor sensitivity (approximately 60%) of the main diagnostic test that is used in most of the high TB prevalence areas of the world (microscopic sputum examination for acid-fast bacilli). In addition, sputum culture, although more sensitive, is expensive and has a long turnaround time (it takes several days to weeks to obtain a culture result). Furthermore, patient samples often have to be transported to centralized laboratories to perform these tests which may result in the loss of samples or results and the transportation leads in logistical challenges. Interferon gamma release assays (IGRAs), including the QuantiFERON® TB Gold In Tube (QFT) accurately indicate Mycobacterium tuberculosis (Mtb) infection but do not discriminate between latent Mtb infection (LTBI) and active TB disease. LTBI is inactive and asymptomatic and requires very different management to active disease. As approximately one third of the world population is latently infected with Mtb the IGRA tests have very limited application in the diagnosis of active TB in resource limited areas, where most of the TB cases occur. We therefore urgently need new diagnostic tests for active TB. One of our research efforts is directed at finding biosignatures consisting of host molecules that will identify different infection and disease states.

Surrogate Markers

Assessment of the response to 6-month antituberculous chemotherapy is complicated as we are lacking suitable tests to identify bacterial killing and especially sterilizing cure. We are trying to find sets of markers, be they clinical, immunological or bacteriological that can be used to predict which patients will respond poorly or even have a relapse after completion of TB therapy. We also investigate mycobacterial factors that might contribute to persistence of disease and/or treatment failure.

 

Host Genetics of TB

 Prof Eileen Hoal (egvh@sun.ac.za)

​Although one third of the world's population is infected with M. tuberculosis, the vast majority will never develop any clinical disease. Inter-individual variation in the immune response plays a major role in determining different clinical outcomes in infected persons. Our aim is to identify these unknown host genetic factors influencing immunity. A better understanding of the pathogenesis of tuberculosis in humans would enable novel approaches to prevention and therapy. We have used whole genome scans, linkage studies, candidate gene association studies and intermediate phenotype investigations to find genes influencing susceptibility to TB in a population with a very high incidence of TB. We recently found two loci influencing reaction to the tuberculin skin test. We are also investigating gene-gene interactions and aim to take this work to the functional level.

Clinical Trials

Prof Andreas Diacon (ahd@sun.ac.za)

​The Western Cape of South Africa rates among the regions with the highest tuberculosis incidence worldwide. We combine the Department's academic expertise with our active trial sites to perform clinical trials with fast recruitment at the highest quality standards. We have in- and outpatient facilities for GCP-compliant phase I, II and III clinical trials and can also perform diagnostic studies or vaccine trials. Our most recent work includes early clinical trials with the novel anti-tuberculosis agents TMC-207, OPC-67683, PA-824 and SQ-109.