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PART IIIA, Nobody does it better: Mycobacterium tuberculosis and persistence

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It is generally assumed that persisters are non-replicating or just slowly growing. However, besides this type of persistence, there are other possible pathways, namely L-form conversion by which tubercle bacilli can persist within the body for a long period harboring latent tuberculosis but without stopping to replicate.

--Nadya Markova, M.D., Ph.D. (Personal Communication), Bulgarian Academy of Sciences in Sofia, Bulgaria.

Nadya Markova, M.D., Ph.D. is an associate professor in the Department of Pathogenic Bacteria, Institute of Microbiology, Bulgarian Academy of Sciences in Sofia, Bulgaria. As a medical doctor and microbiologist, Dr. Markova has dedicated herself to understanding bacterial L-forms, particularly in the context of TB, from epidemiology to mechanisms of dormancy and persistence.

Dr. Markova suggests that there are other possible pathways, namely L-form conversion, by which tubercle bacilli can persist within the body for a long period harboring latent tuberculosis but without stopping to replicate. First isolated and described by Emmy Klieneberger-Nobel in 1935 at the Lister Institute, L-forms reflect a bacterial morphological change characterized by the lack of rigid cell walls. L-forms constitute a phase of bacterial life cycle described as the “L-cycle.”

The current focus of Dr. Markova’s laboratory is to study the unusual biology of mycobacterial cell wall deficient L-forms and to understand in depth the mechanisms of their formation as well as reversion to classical forms. According to Dr. Markova, an L-forms expert, L-forms behave like an entire population within various cells and elements (giant filaments, large “mother” cells and elementary bodies, vesicles, granules and filterable forms, and membranous structures) that are interrelated and interact in various ”disintegrating” or “reintegrating” processes. In fact, the population of L-forms permits certain survival advantages and is an arsenal of reserves to environmental assaults and unfavorable conditions.

Dr. Markova defines persistence as “the ability of bacteria or a small bacterial population, in particular, TB bacilli, to exist or remain alive in infected hosts for a long period of time, in the face of damaging stressful conditions such as antimicrobial agents/antibiotics or host immune factors.” In general, antibiotics act on replicating cells, which may partially account for the tolerance of persisters.

Is the term “bacterial dormancy” interchangeable with “persistence”? Generally, persistence is a more comprehensive term including different states and circumstances related to persistent bacteria, states Dr. Markova. Bacterial dormancy or non-replicating bacteria with low metabolic activity represent one of these states. Thus, the terms “persistence” and “dormancy” are not interchangeable.

Our experiments show that, L-form conversion usually occurs at high cell density under stress treatments. Bacteria undergo drastic morphological and functional changes leading to newly morpho-functionally reorganized microbial ‘‘society’’ which continues to exist and replicate by unusual modes. --Nadya Markova, M.D., Ph.D. (Personal Communication)

Dr. Markova states, “I would like to say that we have successful trials with experimental animals, which suggest the relevance of L-forms to persistence. So formation of persistent mycobacterial L-forms in vivo were demonstrated by means of biological experiments on guinea pigs and rats (Markova et al. 2008a; 2008b). The established by us rat model of experimental tuberculosis mimicked entry into latent infection. Conversion of M. bovis BCG to cell wall deficient forms (L-forms) inside macrophages was observed in experiments with guinea pigs, and it was found that this phenomenon significantly enhanced survival and persistence capability of mycobacteria.”

References and read-more-about-it:

  1. Markova N, Slavchev G, Michailova L. (2012) Filterable forms and L-forms of Mycobacterium bovis BCG: impact for live vaccine features. Hum Vaccin Immunother. Jun;8(6):759-64.
  2. Markova N, Slavchev G, Michailova L. (2012) Unique biological properties of Mycobacterium tuberculosis L-form variants: impact for survival under stress. Int Microbiol. Jun;15(2):61-8.
  3. Markova N. (2009) Hidden face of tuberculosis. Bioscience Hypotheses 2:441-442.
  4. Michailova L, Kussovski V, Radoucheva T, Jourdanova M, Berger W, Rinder H, Markova N. (2005) Morphological variability and cell-wall deficiency in Mycobacterium tuberculosis ‘heteroresistant’ strains. Int j tuberc lung dis 9(8):907–914.
  5. Markova N, Slavchev G, Michailova L, Jourdanova M. (2010) Survival of Escherichia coli under lethal heat stress by L-form conversion. Int J Biol Sci. 6(4):303-315.
  6. L-forms Virtual Home. Dr. Nadya Markova. Available at: https://sites.google.com/site/nadyamarkova/ Accessed 15 February 2013.

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