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Infection and Immunity, January 2005, p. 546-551, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.546-551.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Replication Dynamics of Mycobacterium tuberculosis in Chronically Infected Mice{dagger}

Ernesto J. Muñoz-Elías,{ddagger} Juliano Timm,{ddagger} Tania Botha,§ Wai-Tsing Chan, James E. Gomez, and John D. McKinney*

Laboratory of Infection Biology, The Rockefeller University, New York, New York

Received 30 May 2004/ Returned for modification 26 July 2004/ Accepted 13 September 2004

The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy. In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria. This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing. A static model predicts a close correspondence between "viable counts" (live bacteria) and "total counts" (live plus dead bacteria) in the lungs over time. A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria. Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR. We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time. Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ. These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.

* Corresponding author. Mailing address: Laboratory of Infection Biology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-7081. Fax: (212) 327-7083. E-mail: mckinney{at}rockefeller.edu.

{dagger} This study is dedicated to Philip D'Arcy Hart, whose pioneering research has inspired several generations of TB researchers.

Editor: S. H. E. Kaufmann

{ddagger} E.J.M.-E. and J.T. contributed equally to this work.

§ Present address: Department of Health Sciences, Faculty of Applied Sciences, Cape Technikon, Cape Town, South Africa.

Present address: Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536.

Infection and Immunity, January 2005, p. 546-551, Vol. 73, No. 1
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.1.546-551.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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