The role of trehalose dimycolate (cord factor) on morphology of virulent M. tuberculosis in vitro

Hunter, Robert L.; Venkataprasad, N.; Olsen, Margaret

doi:10.1016/j.tube.2005.08.017

Cited by 46 publications

(37 citation statements)

References 20 publications

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“…In M. tuberculosis complex strains, microscopic cording observed in liquid medium by optical microscopy has been correlated with highly textured colonies that form many wrinkles or serpentines when grown on agar surfaces (9,13,16). This pattern of growth has also been described in M. abscessus (12).…”

Section: Discussionmentioning

confidence: 84%

“…The discovery that virulent tubercle bacilli grew on the surface of a liquid medium, forming veils that spread uniformly over the entire surface of the liquid medium, and climbed up the sides of the glass container, was first described by Koch in 1884 and later by others as a typical characteristic of M. tuberculosis complex strains. Cording in these pellicles was observed by optical microscopy and traditional stains (9,13,15,16,19). The formation of spreading pellicles has been extensively studied in the nonpathogenic species M. smegmatis, in which it has been related to iron availability, synthesis of short-chain mycolic acids, and synthesis of mycolyl-diacylglycerols (4,18).…”

Section: Discussionmentioning

confidence: 99%

“…S3 in the supplemental material). Cording has previously been studied only with optical microscopy, using mainly Ziehl-Neelsen, Kinyoun, and auramine rhodamine stains (9,13,24). In this work, SEM was applied to the study of cords for the first time, providing the first images that enable the ultrastructure of these characteristic formations to be observed.…”

Section: Discussionmentioning

confidence: 99%

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Microscopic Cords, a Virulence-Related Characteristic of Mycobacterium tuberculosis , Are Also Present in Nonpathogenic Mycobacteria

et al. 2010

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The aggregation of mycobacterial cells in a definite order, forming microscopic structures that resemble cords, is known as cord formation, or cording, and is considered a virulence factor in the Mycobacterium tuberculosis complex and the species Mycobacterium marinum. In the 1950s, cording was related to a trehalose dimycolate lipid that, consequently, was named the cord factor. However, modern techniques of microbial genetics have revealed that cording can be affected by mutations in genes not directly involved in trehalose dimycolate biosynthesis. Therefore, questions such as "How does mycobacterial cord formation occur?" and "Which molecular factors play a role in cord formation?" remain unanswered. At present, one of the problems in cording studies is the correct interpretation of cording morphology. Using optical microscopy, it is sometimes difficult to distinguish between cording and clumping, which is a general property of mycobacteria due to their hydrophobic surfaces. In this work, we provide a new way to visualize cords in great detail using scanning electron microscopy, and we show the first scanning electron microscopy images of the ultrastructure of mycobacterial cords, making this technique the ideal tool for cording studies. This technique has enabled us to affirm that nonpathogenic mycobacteria also form microscopic cords. Finally, we demonstrate that a strong correlation exists between microscopic cords, rough colonial morphology, and increased persistence of mycobacteria inside macrophages.Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), killed 1.5 million people in 2006. A further 200,000 HIV-positive people died from HIV-associated TB (http://www.who.int/tb/en/index.html). Intensive research into the virulence factors that determine the pathogenicity of M. tuberculosis have been carried out since the tubercle bacillus was discovered. Unfortunately, despite the knowledge obtained, the factors that make M. tuberculosis virulent have not yet been identified (23,29). One of the first phenotypic characteristics linked to virulence was the microscopic formation of cords. When M. tuberculosis cells grow in a liquid medium without detergent, they form tight bundles, or cords, consisting of bacilli in which the orientation of the long axis of each cell is parallel to the long axis of the cord. M. tuberculosis microscopic cords were first observed by Robert Koch in 1882, but knowledge of their significance increased in 1947 with studies by Middlebrook et al. (16). These authors compared the virulent H37Rv and avirulent H37Ra M. tuberculosis strains and found that the formation of cords took place only in the virulent strain, whereas cells from the avirulent H37Ra strain were not oriented and merely formed irregular clumps. In 1953, Bloch isolated a toxic glycolipid from M. tuberculosis and related it to the virulence of the tubercle bacillus and to cording. Bloch named the glycolipid cord factor, and later, it was identified as trehalose dimycolate (TDM) (2, 17). However, 56...

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Microscopic Cords, a Virulence-Related Characteristic of Mycobacterium tuberculosis , Are Also Present in Nonpathogenic Mycobacteria

et al. 2010

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“…TDMs are believed to play a particularly important role in determining colony characteristics and cording (31), and the observed changes in colony morphology and cording in the ⌬kasB mutant were thus likely a direct or indirect effect of the altered MA profile of the TDMs produced by the mutant. Loss of cording is often associated with decreased virulence (19), and indeed this was the case with the ⌬kasB mutant.…”

Section: Discussionmentioning

confidence: 99%

Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immunocompetent mice

Bhatt

Fujiwara

Bhatt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

181

174

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Mycobacterium tuberculosis, the causative agent of tuberculosis, has two distinguishing characteristics: its ability to stain acid-fast and its ability to cause long-term latent infections in humans. Although this distinctive staining characteristic has often been attributed to its lipid-rich cell wall, the specific dye-retaining components were not known. Here we report that targeted deletion of kasB, one of two M. tuberculosis genes encoding distinct ␤-ketoacyl-acyl carrier protein synthases involved in mycolic acid synthesis, results in loss of acid-fast staining. Biochemical and structural analyses revealed that the ⌬kasB mutant strain synthesized mycolates with shorter chain lengths. An additional and unexpected outcome of kasB deletion was the loss of ketomycolic acid trans-cyclopropanation and a drastic reduction in methoxymycolic acid trans-cyclopropanation, activities usually associated with the trans-cyclopropane synthase CmaA2. Although deletion of kasB also markedly altered the colony morphology and abolished classic serpentine growth (cording), the most profound effect of kasB deletion was the ability of the mutant strain to persist in infected immunocompetent mice for up to 600 days without causing disease or mortality. This long-term persistence of ⌬kasB represents a model for studying latent M. tuberculosis infections and suggests that this attenuated strain may represent a valuable vaccine candidate against tuberculosis. mycolic acid ͉ Ziehl-Neelsen stain ͉ cording ͉ persistence ͉ FAS-II

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“…However, these biological properties were soon found to be dependent upon isolation, formulation and administration methodologies. While TDM has additional properties beyond its contribution to organism morphology [20], yet direct understanding of its role in clinical disease remains elusive.…”

Section: Biological Properties Associated With Cord Factormentioning

confidence: 99%

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

Actor¹

2012

Mycobact Diseases

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The role of trehalose dimycolate (cord factor) on morphology of virulent M. tuberculosis in vitro

Cited by 46 publications

References 20 publications

Microscopic Cords, a Virulence-Related Characteristic of Mycobacterium tuberculosis , Are Also Present in Nonpathogenic Mycobacteria

Microscopic Cords, a Virulence-Related Characteristic of Mycobacterium tuberculosis , Are Also Present in Nonpathogenic Mycobacteria

Deletion of kasB in Mycobacterium tuberculosis causes loss of acid-fastness and subclinical latent tuberculosis in immunocompetent mice

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

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