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

Apoorva Bhatt, Nagatoshi Fujiwara, Kiranmai Bhatt, Sudagar S. Gurcha, Laurent Kremer, Bing Chen, John Chan, Steven A. Porcelli, Kazuo Kobayashi, Gurdyal S. Besra, William R. Jacobs

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

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 β-ketoacyl- acyl carrier protein synthases involved in mycolic acid synthesis, results in loss of acid-fast staining. Biochemical and structural analyses revealed that the ΔkasB 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 methoxy-mycolic 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 ΔkasB represents a model for studying latent M. tuberculosis infections and suggests that this attenuated strain may represent a valuable vaccine candidate against tuberculosis.

Original languageEnglish (US)
Pages (from-to)5157-5162
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number12
DOIs
StatePublished - Mar 20 2007

Keywords

  • Cording
  • FAS-II
  • Mycolic acid
  • Persistence
  • Ziehl-Neelsen stain

ASJC Scopus subject areas

  • General

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