Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of Growth and Cytokine Induction in Human Monocyte-Derived Macrophages
Nicol MP (2012) Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of
Growth and Cytokine Induction in Human Monocyte-Derived Macrophages. PLoS ONE 7(8): e43170. doi:10.1371/journal.pone.0043170
Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of Growth and Cytokine Induction in Human Monocyte-Derived Macrophages
Rajesh Sarkar 0
Laura Lenders 0
Katalin A. Wilkinson 0
Robert J. Wilkinson 0
Mark P. Nicol 0
Olivier Neyrolles, Institut de Pharmacologie et de Biologie Structurale, France
0 1 Division of Medical Microbiology, University of Cape Town , Cape Town , South Africa , 2 National Health Laboratory Services, Groote Schuur Hospital , Cape Town , South Africa , 3 Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town , South Africa , 4 Division of Medicine, Imperial College London , London , United Kingdom , 5 MRC National Institute for Medical Research , Mill Hill, London , United Kingdom
Background: Strains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis. Methods: Strains from two major modern lineages (lineage 2 [East-Asian] and lineage 4 [Euro-American]) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 [CAS/Delhi]) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction. Results: In liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p = 0.0024; lineage 4 vs. lineage 3 p = 0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte-derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p,0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40. Conclusions: Strains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of these strains in different human populations.
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Funding: Funding for R.J. Wilkinson from Wellcome Trust (084323 and 088316) and Medical Research Council (U.1175.02.002.00014.01), the Wellcome Trust
(085251/Z/08/Z), and the National Research Foundation of South Africa. The funders had no role in study design, data collection and analysis, decision to publish,
or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB),
infects over 2 billion people world-wide and causes 1.7 million
deaths annually [1]. The clinical significance of strain variation in
M. tuberculosis remains controversial, partly since virulence cannot
be simply defined in relation to defined virulence characteristics as
in other bacterial pathogens, such as Clostridium tetani or
Staphylococcus aureus. Since modern M. tuberculosis evolves through
single nucleotide substitutions, deletion and duplication events, the
population structure is strongly clonal [2]. It is therefore feasible
that such clonal lineages may evolve specific virulence
characteristics [3].
In a robust phylogenetic study based on genomic deletion
analysis, M. tuberculosis has been classified into six major lineages.
These lineages are highly predominant in specific geographic areas
and named according to their geographical distribution: Lineage 1
(also known as Indo-Oceanic lineage), Lineage 2 (also known as
East Asian; includes Beijing), Lineage 3 (also known as CAS/
Delhi), Lineage 4 (also known as Euro-American), Lineage 5 (also
known as West African 1) and Lineage 6 (also known West African
2). In the Western Cape region of South Africa the Lineage 2
(East Asian; includes Beijing) and Lineage 4 (Euro-American;
includes LAM3/F11 strains) lineages predominate [4,5,6,7].
Macrophages are the primary site of intracellular replication of
M. tuberculosis. In hum (...truncated)