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Deletion of Kasb in Mycobacterium Tuberculosis Causes Loss of Acid-Fastness and Subclinical Latent Tuberculosis in Immunocompetent Mice

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Deletion of Kasb in Mycobacterium Tuberculosis Causes Loss of Acid-Fastness and Subclinical Latent Tuberculosis in Immunocompetent Mice 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. Gurchaʈ, Laurent Kremer**, Bing Chen*†, John Chan†, Steven A. Porcelli†, Kazuo Kobayashi§, Gurdyal S. Besraʈ, and William R. Jacobs, Jr.*†,†† *Howard Hughes Medical Institute and †Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; §Department of Host Defense, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; ʈSchool of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; and **Laboratoire de Dynamique Mole´culaire des Interactions Membranaires, Centre National de la Recherche Scientifique, Unite´Mixte de Recherche 5539, Universite´de Montpellier II, 34095 Montpellier Cedex 5, France Edited by Barry R. Bloom, Harvard School of Public Health, Boston, MA, and approved February 1, 2007 (received for review October 2, 2006) Mycobacterium tuberculosis, the causative agent of tuberculosis, very-long-chain ␣-alkyl ␤-hydroxy fatty acids that are either has two distinguishing characteristics: its ability to stain acid-fast esterified to peptidoglycan-linked arabinogalactan or present as and its ability to cause long-term latent infections in humans. a part of the interspersed glycolipid, trehalose dimycolate Although this distinctive staining characteristic has often been (TDM) (9, 10). The long mero-MA chain is synthesized by a attributed to its lipid-rich cell wall, the specific dye-retaining multienzyme fatty acid synthase II complex (FASII) from acyl components were not known. Here we report that targeted dele- carrier protein (ACP)-bound substrates that are elongated by tion of kasB, one of two M. tuberculosis genes encoding distinct repetitive reductive cycles, the first step of which is catalyzed by ␤-ketoacyl- acyl carrier protein synthases involved in mycolic acid a ␤-ketoacyl-ACP synthase. In M. tuberculosis and other myco- synthesis, results in loss of acid-fast staining. Biochemical and bacteria, two genes, kasA and kasB, encode distinct FASII structural analyses revealed that the ⌬kasB mutant strain synthe- ␤-ketoacyl-ACP synthases (11). Whereas kasA is an essential sized mycolates with shorter chain lengths. An additional and gene (12), kasB is not essential for normal mycobacterial growth unexpected outcome of kasB deletion was the loss of ketomycolic in Mycobacterium marinum and Mycobacterium smegmatis (12, acid trans-cyclopropanation and a drastic reduction in methoxy- 13), suggesting that kasB might be an accessory gene that is not mycolic acid trans-cyclopropanation, activities usually associated essential for MA biosynthesis. Previous in vitro (14) and in vivo with the trans-cyclopropane synthase CmaA2. Although deletion (13) results had indicated that whereas KasA is involved in the of kasB also markedly altered the colony morphology and abol- initial elongation of the mero chain, KasB might be responsible ished classic serpentine growth (cording), the most profound effect for its extension to full-length mero-MAs. of kasB deletion was the ability of the mutant strain to persist in Before this work, the effects of kasB deletion in M. tuberculosis infected immunocompetent mice for up to 600 days without were unknown, and the role of KasB in pathogenesis had not causing disease or mortality. This long-term persistence of ⌬kasB been investigated in an animal model of infection. In this work, represents a model for studying latent M. tuberculosis infections we have shown that the deletion of kasB caused alterations in and suggests that this attenuated strain may represent a valuable MAs that resulted in a loss of acid-fastness. Furthermore, the M. vaccine candidate against tuberculosis. tuberculosis ⌬kasB mutant was analyzed after infections of both immunocompromised and immunocompetent mice, which re- mycolic acid ͉ Ziehl-Neelsen stain ͉ cording ͉ persistence ͉ FAS-II vealed a marked attenuation of in vivo growth in the mutant that led to a long-term persistent infection that resembled latent he Ziehl–Neelsen stain-based microscopic detection of My- tuberculosis. These results provide insights into the nature of the MICROBIOLOGY Tcobacterium tuberculosis, which relies on the acid-fast at- clinically important feature of acid-fast staining in M. tubercu- tribute of the tubercle bacillus, remains the cornerstone of losis and are also relevant to understanding and modeling latent diagnosis of tuberculosis (TB), particularly in poor countries tuberculosis. where the infection is highly prevalent (1). This staining method Results was developed by Ziehl and Neelsen who improvised on the early work of Koch, Rindfleisch, and Ehrlich (2–4). Acid-fastness has Deletion of kasB Caused a Change in Mycobacterial Colony Morphol- ogy and Loss of Cording and Acid-Fastness. A specialized transduc- been attributed to a number of mycobacterial cell wall compo- ⌬ nents, including outer lipids, arabinogalactan-bound mycolic ing phage, ph kasB, containing an allelic exchange substrate acids (MAs), and free hydroxyl and carboxylate groups of cell designed to replace kasB with a hygromycin resistance cassette wall lipids (5–7). The underlying theme in all of the proposed mechanisms was the presence of a lipid-rich, hydrophobic barrier Author contributions: A.B., J.C., S.A.P., G.S.B., and W.R.J. designed research; A.B., N.F., K.B., that could be penetrated by phenol-based stains but was resistant S.S.G., L.K., and B.C. performed research; K.K. and W.R.J. contributed new reagents/analytic to decolorization by acid-alcohol. However, the precise molec- tools; A.B., N.F., and K.B. analyzed data; and A.B. and W.R.J. wrote the paper. ular component responsible for this unique staining property has The authors declare no conflict of interest. never been identified. This article is a PNAS direct submission. Early studies on the effects of isoniazid on the staining Abbreviations: ACP, acyl carrier protein; FASII, fatty acid synthase II complex; MA, mycolic characteristics of tubercle bacilli demonstrated a loss of acid- acid; MAME, mycolic acid methyl ester; TB, tuberculosis; TDM, trehalose dimycolate. fastness after growth in the presence of the antibiotic (8). ‡Present address: School of Biosciences, University of Birmingham, Edgbaston, Birmingham Because isoniazid was known to inhibit the synthesis of MAs, the B15 2TT, United Kingdom. major class of lipids composing the cell wall of mycobacteria, this ¶Present address: School of Medicine, St. George’s University, Grenada, West Indies. result suggested that these molecules may be the components ††To whom correspondence should be addressed. E-mail: [email protected]. responsible for the acid-fast staining characteristic and that This article contains supporting information online at www.pnas.org/cgi/content/full/ mutants defective in MA biosynthesis would be reasonable 0608654104/DC1. candidates to study the phenomenon of acid-fastness. MAs are © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608654104 PNAS ͉ March 20, 2007 ͉ vol. 104 ͉ no. 12 ͉ 5157–5162 Downloaded by guest on September 27, 2021 Fig. 1. Generation of a M. tuberculosis kasB mutant. (A) Map of the M. tuberculosis kasB region in WT and ⌬kasB strains. [␣-32P]dCTP-labeled probes were derived from Ϸ500-bp upstream and downstream flanking sequences that were used to construct the knockout plasmids, and they are indicated by thick lines with square ends. The PvuII-digested fragments expected in a Southern blot are indicated by gapped lines with sizes. (B) Southern blot of PvuII-digested genomic DNA from WT and ⌬kasB strains. Only one representative band pattern is shown for each mutant strain of H37Rv and CDC1551; res, ␥␦-resolvase site; hyg, hygromycin resistance gene. (hyg), was transduced into two virulent M. tuberculosis strains, staining of cultures by two different methods (Kinyoun stain or H37Rv (laboratory strain) and CDC1551 (clinical isolate). TB-fluorescent stain), which revealed that the ⌬kasB strain had lost Southern blot analysis of genomic DNA isolated from hygro- the ability to retain the primary stain after washing with the mycin-resistant (HygR) colonies confirmed replacement of kasB acid-alcohol decolorizer (one staining method is shown in Fig. 3). with hyg (Fig. 1). For further studies, we chose the kasB mutant These results suggested that the change in morphology was likely generated in the clinical strain CDC1551; the CDC1551 parental due to a change in the cell wall MA content and correlated well with strain, the ⌬kasB mutant strain, and the complemented strain the increased sensitivity of the ⌬kasB strain to the lipophilic will be referred to here as WT (wild-type), ⌬kasB, and antibiotic rifampicin (data not shown). The mutant strain was also ⌬kasB(pMV261kasB), respectively. Deletion of kasB resulted in more sensitive to the KasA/KasB inhibitor thiolactomycin [mini- a striking alteration in colony morphology, with the mutant mum inhibitory concentration (MIC) Ͻ1 ␮g/ml] than the WT strain strain forming colonies much smaller than those of the parental (MIC ϭ 5 ␮g/ml). strain (Fig. 2). In addition, colonies of mutant strain appeared to have a different surface texture. The smaller size of the MA Chain Length and Cyclopropanation Are Altered in the ⌬kasB colonies was not the result of a slower growth rate because the Mutant. The changes in cording and in the acid-fast staining
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