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Journal of Bacteriology, September 2000, p. 4889-4898, Vol. 182, No. 17
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Stringent Response of Mycobacterium
tuberculosis Is Required for Long-Term Survival
Todd P.
Primm,1
Susan J.
Andersen,2
Valerie
Mizrahi,2
David
Avarbock,3
Harvey
Rubin,3,* and
Clifton
E.
Barry III1,*
Tuberculosis Research Section, Laboratory of
Host Defenses, National Institute of Allergy and Infectious Diseases,
National Institutes of Health, Bethesda, Maryland
20852,1 Division of Infectious Diseases,
Department of Medicine, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104,3
and MRC/SAIMR/WITS Molecular Mycobacteriology Research
Unit, South African Institute for Medical Research, and Department
of Molecular Medicine and Hematology, University of Witwatersrand
Medical School, Johannesburg, South Africa2
Received 11 April 2000/Accepted 16 June 2000
The stringent response utilizes hyperphosphorylated guanine
[(p)ppGpp] as a signaling molecule to control bacterial gene
expression involved in long-term survival under starvation conditions.
In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium
tuberculosis contains a single homolog of these proteins
(RelMtb) and responds to nutrient starvation by producing
(p)ppGpp. A relMtb knockout strain
was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The relMtb
mutant displayed a significantly slower aerobic growth rate than the
wild type in synthetic liquid media, whether rich or minimal. The
growth rate of the wild type was equivalent to that of the mutant
when citrate or phospholipid was employed as the sole carbon
source. These two organisms also showed identical growth rates within a
human macrophage-like cell line. These results suggest that the in vivo
carbon source does not represent a stressful condition for the bacilli,
since it appears to be utilized in a similar
RelMtb-independent manner. In vitro growth in liquid
media represents a condition that benefits from
RelMtb-mediated adaptation. Long-term survival of the
relMtb mutant during in vitro starvation or
nutrient run out in normal media was significantly impaired compared to
that in the wild type. In addition, the mutant was significantly less
able to survive extended anerobic incubation than the wild-type
virulent organism. Thus, the RelMtb protein is required for
long-term survival of pathogenic mycobacteria under starvation conditions.
*
Corresponding author. Mailing address for C. E. Barry III: Tuberculosis Research Section, LHD/NIAID, National
Institutes of Health, Twinbrook II, Room 239, 12441 Parklawn Dr.,
Rockville, MD 20852. Phone: (301) 435-7509. Fax: (301) 402-0993. E-mail: clifton_barry{at}nih.gov. Mailing address for
H. Rubin: University of Pennsylvania, 225 Johnson Pavilion,
Philadelphia, PA 19104. Phone: (215) 662-6475. Fax: (215) 662-7842. E-mail: rubinh{at}mail.med.upenn.edu.
Journal of Bacteriology, September 2000, p. 4889-4898, Vol. 182, No. 17
0021-9193/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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