Thesis (PhD)--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: The tuberculosis (TB) incidence has increased in Southern Africa and the situation
is worsened by the emergence of drug-resistant Mycobacterium tuberculosis strains.
Molecular biological techniques have been used to understand the disease dynamics of
TB. In a series of studies we describe the use of these techniques to understand the
disease dynamics of TB in Southern Africa.
Using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) to
characterize M. tuberculosis strains from TB patients in Zimbabwe, we identified a
genotype causing a disproportionate number of TB cases. The genotype belonged to the
Latin American Mediterranean (LAM) lineage and we named it the Southern Africa1
(SAF1) family and later renamed it SAF1/RDRio, also reflecting its predominance in
South America. To establish if this family of strains was predominant elsewhere in
Southern Africa, genotypes were compared to those from Western Cape, South Africa
and Zambia. The SAF1/RDRio strains were highly prevalent in Zambia but were only a
minor fraction of the strains in South Africa. The geographical distribution of
SAF1/RDRio strains was determined in Gweru, Zimbabwe, and was found to be spread in
high incidence areas. From these two studies it was hypothesized that certain host and
bacterial factors were associated with disease due to SAF1/RDRio.
Subsequently potential risk factors and clinical outcomes of disease due to SAF1/RDRio
strains were explored. An association was found with smoking and cavitary pulmonary
disease suggesting that SAF1/RDRio caused a more severe and highly transmissible
formof TB Using IS6110-RFLP, principal genetic grouping, spoligotyping, IS6110 insertion-site
mapping and variable-number tandem repeats (VNTR) typing, low IS6110 copy clade
(LCC) identified in Zimbabwe were characterized and compared to the strains from Cape
Town, South Africa and other regions. The LCC strains from Cape Town, South Africa,
were found to have close evolutionary relationship with strains from Zimbabwe and other
regions and were widely distributed suggesting they play an important role in the global
TB epidemic.
Observations from these studies and those from other studies led to the hypothesis that
specific genotypes of M. tuberculosis predominate in regions of Southern Africa. To gain
an insight on the population structure of M. tuberculosis strains in Southern Africa,
spoligotyping and/or IS6110-RFLP data from eight countries were compared. This is the
first study to describe the M. tuberculosis population structure in Southern Africa.
Distinct genotypes were associated with specific geographic regions. These findings have
important implications for TB diagnostics, anti-TB drug and vaccine development.
The population structure of multidrug-resistant (MDR), pre-extensively drug-resistant
(pre-XDR) and extensively drug-resistant (XDR) M. tuberculosis isolates from provinces
in South Africa was also determined. This is again the first study to describe the
population structure of drug-resistant M. tuberculosis in South Africa. The results also
showed geographic localization of genotypes and an association with resistance class.
However, decreasing strain diversity was observed as the isolates evolved from MDR-TB
to XDR-TB suggesting selection for the specific genotypes. These findings highlight the importance of identifying genetic markers in drug-resistant strains, to enhance early
detection of those at risk of developing XDR-TB. / AFIKAANSE OPSOMMING: Die voorkoms van tuberkulose (TB) in Suider Afrika word vererger deur stamme van
Mycobacterium tuberculosis wat weerstandig is teen die beskikbare anti-tuberkulose
middels. Molekulêre tegnieke word gebruik om in hierdie reeks studies die dinamika van
TB in Suider Afrika te ondersoek
Deur spoligotipering en IS6110 restriksie fragment lengte polimorfisme (RFLP) tegnieke
te gebruik om M. tuberculosis stamme van pasiente in Zimbabwe te beskryf, het ons ‘n
genotipe gevind wat ‘n buitengewone aantal TB gevalle veroorsaak het. Hierdie genotipe
is deel van die internasionaal beskryfde Latyns Amerikaase en Meditereense (LAM) stam
familie. Ons het dit die Suider Afrikaanse Familie1 (SAF1) genoem, maar later hernoem
na SAF1/RDRio, omdat dieselfde genotipe in ook volop is in Suid Amerika. Om vas te stel
of hierdie familie ook oorheesend is in die res van Suider Afrika, is dit vergelyk met
beskikbare databasisse van die Wes-Kaap, Suid-Afrika en Zambië. Alhoewel
SAF1/RDRio in die Wes-Kaap gevind is, dra dit slegs tot ‘n mindere mate by tot die
plaaslike TB epidemie. Aan die anderkant kom SAF1/RDRio baie algemeen in Zambië
voor. ‘n Verdere studie wys ook dat die SAF1/RDRio familie eweredig en wyd verspreid
voorkom in hoë insidensie gebiede in Gweru, Zimbabwe. Vanuit die bevindings van
hierdie 2 studies, kan ons aflei dat sekere gasheer- en bakteriële eienskappe geassosieer is
met SAF1/RDRio-TB-infeksie.
Hierna is potensiële risiko faktore en kliniese uitkomste van siekte as gevolg van infeksie
met SAF1/RDRio ondersoek. ‘n Assosiasie met rook en kaviterende pulmonale infeksie is gevind,wat daarop dui dat SAF1/RDRio erger vorm van TB veroorsaak en hoogs
oordraagbaar is.
Deur gebruik te maak van IS6110- (RFLP), hoof groep groepering, spoligotipering,
IS6110 invoegings kaartering en veranderlike getal tandem herhaling (VNTR) tipering
kon lae IS6110 invoeginsgetal (LCC) stamme van Kaapstad, Zimbabwe en ander gebiede
vergelyk word. Al die LCC stamme in die studie is evolusionêr naby verwant aan mekaar
en is wyd verspreid, wat dui op hulle belangrike rol in die wêreldwye TB epidemie.
Waarnemings in hierdie asook ander studies het tot die hipotese gely dat spesifieke
genotipes van M. tuberculosis dominant is in verskillende gebiede van Suider Afrika. Om
meer insig tot die populasie samestelling van M. tuberculosis stamme in Suider Afrika in
te win is spoligotipes en RFLP-data van 8 lande vergelyk. Hierdie is die eerste studie om
die populasie samestelling van M. tuberculosis in Suider Afrika te beskryf en is
belangrike fir toekomstige ontwikkeling van nuwe TB diagnose tegnieke, anti-TB
middels en TB entstowwe.
Die populasie samestelling van multiweerstandige (MDR), pre-ekstreme weerstandige
(pre-XDR) en ekstreme weerstandige (XDR) M. tuberculosis van verskillende provinsies
in Suid-Afrika is ook bepaal. Hierdie studie is ook die eerste wat die populasie
samestelling van weerstandige M. tuberculosis in Suid-Afrika beskryf. Die resultate wys
geografiese lokalisering van genotipes en ‘n assosiasie met weerstandigheidsklas. ‘n
Afname in stam diversiteit soos die isolate van MDR-TB tot XDR-TB ontwikkel, dui op seleksie van spesifieke genotipes. Hierdie bevinding lê die klem op die belangrikheid van
die identifisering van genetiese merkers in weerstandige stamme om die risiko vir die
ontwikkeling van XDR-TB te verminder deur vroë deteksie.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/6902 |
| Date | 03 1900 |
| Creators | Chihota, Violet |
| Contributors | Warren, Robin M., Van Helden, Paul D., University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | x, 228 p. : col. ill. |
| Rights | Stellenbosch University |
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