Fitness of multi-and extensively drug-resistant mycobacterium tuberculosis clinical strains.
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Date
2015
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Abstract
The biological fitness of a pathogen is defined as its ability to reproduce, survive, cause disease
and be transmitted. Drug-resistant M. tuberculosis isolates often exhibit reduced competitive
ability against susceptible isolates in the absence of drug selection. However, compensatory
mutations may, to some extent, offset fitness costs associated with resistance-conferring
mutations. Most studies to date have focused on the fitness of isogenic laboratory strains or
globally-relevant strains. Fewer studies have addressed the fitness of endemic strains which
propagate in multidrug and extensively drug-resistant forms (MDR and XDR, respectively). In
this study, the fitness of four genotypes which drive the transmission of tuberculosis (TB) in
KwaZulu-Natal (KZN), South Africa was explored. This included F15/LAM4/KZN genotype
strains, some of which were involved in the notorious XDR-TB outbreak in Tugela Ferry, KZN
as well as Beijing, F11 and F28 genotype strains. Drug-resistant F15/LAM4/KZN and F28
genotype strains demonstrated increased in vitro fitness, whilst Beijing and F11 MDR strains
had markedly reduced fitness. These findings correlated with whole-genome and Sanger
sequencing data which revealed the presence of low/no-cost resistance-conferring mutations as
well as intra- and intergenic compensatory mutations in drug-resistant F15/LAM4/KZN and F28
strains, respectively. In contrast, high cost katG mutations and no accompanying compensatory
mutations were identified in Beijing and F11 MDR strains. During co-culture experiments, a
novel observation was made whereby susceptible and resistant strains exhibited synergistic
growth compared with axenic cultures i.e. in vitro trans-complementation. Drug-resistant
F15/LAM4/KZN strains did not undergo fitness costs in THP-1 macrophages and produced
increasing levels of TNF-α which may enhance tissue destruction and dissemination to other
hosts. Although demonstrating similar intracellular fitness, susceptible and MDR Beijing, F11
and F28 strains induced heterogeneous cytokine responses. Thus, the lack of a direct
relationship between bacillary burden and cytokine responses indicates that this diversity results
from strain heterogeneity. Relapse isolates, including those from F15/LAM4/KZN and Beijing
genotypes, may reactivate without any changes in biological fitness, thereby retaining the
potential to re-transmit. Taken together, the enhanced fitness of drug-resistant F15/LAM4/KZN
and F28 genotype strains is due to the presence of beneficial mutations, while the reduced
fitness of MDR Beijing and F11 strains is associated with high cost mutations.
Description
Doctor of Philosophy in Medical Microbiology. University of KwaZulu-Natal, Medical School 2015.
Keywords
Mycobacterium tuberculosis., Drug resistance., Theses -- Medical microbiology.