Article thumbnail

Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival

By Susanne Homolka, Stefan Niemann, David G. Russell and Kyle H. Rohde

Abstract

Tuberculosis exerts a tremendous burden on global health, with ∼9 million new infections and ∼2 million deaths annually. The Mycobacterium tuberculosis complex (MTC) was initially regarded as a highly homogeneous population; however, recent data suggest the causative agents of tuberculosis are more genetically and functionally diverse than appreciated previously. The impact of this natural variation on the virulence and clinical manifestations of the pathogen remains largely unknown. This report examines the effect of genetic diversity among MTC clinical isolates on global gene expression and survival within macrophages. We discovered lineage-specific transcription patterns in vitro and distinct intracellular growth profiles associated with specific responses to host-derived environmental cues. Strain comparisons also facilitated delineation of a core intracellular transcriptome, including genes with highly conserved regulation across the global panel of clinical isolates. This study affords new insights into the genetic information that M. tuberculosis has conserved under selective pressure during its long-term interactions with its human host

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2900310
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2007). A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages.
  2. (2004). A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response.
  3. (2007). A highly conserved transcriptional repressor controls a large regulon involved in lipid degradation in Mycobacterium smegmatis and Mycobacterium tuberculosis.
  4. (2003). A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes.
  5. (2002). A new evolutionary scenario for the Mycobacterium tuberculosis complex.
  6. (2004). A promoter mutation causes differential nitrate reductase activity of Mycobacterium tuberculosis and Mycobacterium bovis.
  7. (2010). A single-nucleotide mutation in the -10 promoter region inactivates the narK2X promoter in Mycobacterium bovis and Mycobacterium bovis BCG and has an application in diagnosis.
  8. (1997). An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon.
  9. (2000). Anaerobic nitrate reductase (narGHJI) activity of Mycobacterium bovis BCG in vitro and its contribution to virulence in immunodeficient mice.
  10. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
  11. (2001). Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier.
  12. (1999). Analysis, expression and prevalence of the Mycobacterium tuberculosis homolog of bacterial virulence regulating proteins.
  13. (2005). Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis.
  14. (2007). Beijing family Mycobacterium tuberculosis strains differ in their intracellular growth in THP-1 macrophages.
  15. (2009). Changing Mycobacterium tuberculosis population highlights clade-specific pathogenic characteristics.
  16. (2006). Characterization of mycobacterial virulence genes through genetic interaction mapping.
  17. (1996). Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance.
  18. (2009). Clinical strains of Mycobacterium tuberculosis display a wide range of virulence in guinea pigs. Tuberculosis (Edinb).
  19. (1999). Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice.
  20. (1998). Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages.
  21. (2002). Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific.
  22. (2003). Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis.
  23. (2005). Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes.
  24. (2001). E. coli methionine sulfoxide reductase with a truncated N terminus or C terminus, or both, retains the ability to reduce methionine sulfoxide.
  25. (2005). Effects of genetic variability of Mycobacterium tuberculosis strains on the presentation of disease.
  26. (1999). Enhanced capacity of a widespread strain of Mycobacterium tuberculosis to grow in human macrophages.
  27. (2008). Evolution, population structure, and phylogeography of genetically monomorphic bacterial pathogens.
  28. (2005). Gene expression diversity among Mycobacterium tuberculosis clinical isolates.
  29. (2002). Gene Expression during hostpathogen interactions: approaches to bacterial mRNA extraction and labeling for microarray analysis.
  30. (2002). Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.
  31. (2009). Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints.
  32. (2007). Global phylogeography of Mycobacterium tuberculosis and implications for tuberculosis product development.
  33. (2008). Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon.
  34. (2008). High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography.
  35. (2009). Human genetic influence on susceptibility of tuberculosis: from infection to disease.
  36. (2006). Identification of a respiratory-type nitrate reductase and its role for survival of Mycobacterium smegmatis in Wayne model.
  37. (2008). Identification of Mycobacterium tuberculosis clinical isolates with altered phagocytosis by human macrophages due to a truncated lipoarabinomannan.
  38. (2009). igr Genes and Mycobacterium tuberculosis cholesterol metabolism.
  39. (2005). In vivo phenotypic dominance in mouse mixed infections with Mycobacterium tuberculosis clinical isolates.
  40. (2003). Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program.
  41. (1998). Intracellular gene expression. Analysis of RNA from mycobacteria in macrophages using RT-PCR.
  42. (2007). Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling.
  43. (2004). Macro-array and bioinformatic analyses reveal mycobacterial ‘core’ genes, variation in the ESAT-6 gene family and new phylogenetic markers for the Mycobacterium tuberculosis complex.
  44. (2009). Major Mycobacterium tuberculosis lineages associate with patient country of origin.
  45. (2003). Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis.
  46. (2008). Modeling the effects of strain diversity and mechanisms of strain competition on the potential performance of new tuberculosis vaccines.
  47. (2005). Molecular evolutionary history of tubercle bacilli assessed by study of the polymorphic nucleotide within the nitrate reductase (narGHJI) operon promoter.
  48. (2008). Mycobacterial persistence requires the utilization of host cholesterol.
  49. (2002). Mycobacterium tuberculosis CDC1551 is resistant to reactive nitrogen and oxygen intermediates in vitro.
  50. (2007). Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues.
  51. (2008). Mycobacterium tuberculosis strains disrupted in mce3 and mce4 operons are attenuated in mice.
  52. (2009). Mycobacterium tuberculosis WhiB3 maintains redox homeostasis by regulating virulence lipid anabolism to modulate macrophage response.
  53. (1996). Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis.
  54. (2003). mymA operon of Mycobacterium tuberculosis: its regulation and importance in the cell envelope.
  55. (1998). Nitrate reduction as a marker for hypoxic shiftdown of Mycobacterium tuberculosis.
  56. (2008). Origin, spread and demography of the Mycobacterium tuberculosis complex.
  57. (2009). PapA3 is an acyltransferase required for polyacyltrehalose biosynthesis in Mycobacterium tuberculosis.
  58. (2009). Phthiocerol dimycocerosate transport is required for resisting interferon-gamma-independent immunity.
  59. (2003). Polymorphic nucleotide within the promoter of nitrate reductase (NarGHJI) is specific for Mycobacterium tuberculosis.
  60. (2010). Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains.
  61. (2002). Reactive nitrogen intermediates have a bacteriostatic effect on Mycobacterium tuberculosis in vitro.
  62. (2005). Requirement of the mymA operon for appropriate cell wall ultrastructure and persistence of Mycobacterium tuberculosis in the spleens of guinea pigs.
  63. (2003). Role of narK2X and narGHJI in hypoxic upregulation of nitrate reduction by Mycobacterium tuberculosis.
  64. (2009). Role of the dosR-dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models.
  65. (2003). Rv3133c/ dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis.
  66. (2004). Stable association between strains of Mycobacterium tuberculosis and their human host populations.
  67. (2007). Steyn AJ
  68. (1994). Strains of Mycobacterium tuberculosis differ in susceptibility to reactive nitrogen intermediates in vitro.
  69. (2010). Strains of the East Asian (W/Beijing) lineage of Mycobacterium tuberculosis are DosS/DosT-DosR two-component regulatory system natural mutants.
  70. (1997). Susceptibility of a panel of virulent strains of Mycobacterium tuberculosis to reactive nitrogen intermediates.
  71. (2008). The actinobacterial mce4 locus encodes a steroid transporter.
  72. (2008). The clinical consequences of strain diversity in Mycobacterium tuberculosis.
  73. (2004). The Mycobacterium tuberculosis dosRS two-component system is induced by multiple stresses.
  74. (2001). The Mycobacterium tuberculosis pks2 gene encodes the synthase for the heptaand octamethyl-branched fatty acids required for sulfolipid synthesis.
  75. (2008). The phenolic glycolipid of Mycobacterium tuberculosis differentially modulates the early host cytokine response but does not in itself confer hypervirulence.
  76. (2005). The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth.
  77. (2004). The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis.
  78. (2007). The WBeijing lineage of Mycobacterium tuberculosis overproduces triglycerides and has the DosR dormancy regulon constitutively upregulated.
  79. (2003). Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages: Insights into the Phagosomal Environment.
  80. (2007). Two polyketidesynthase-associated acyltransferases are required for sulfolipid biosynthesis in Mycobacterium tuberculosis.
  81. (2006). Variable host-pathogen compatibility in Mycobacterium tuberculosis.
  82. (2001). Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/ beta.
  83. (2005). Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli.
  84. (2008). Virulence, immunopathology and transmissibility of selected strains of Mycobacterium tuberculosis in a murine model.
  85. (2006). Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages.