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Infection and Immunity, December 2006, p. 6865-6876, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00561-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differences in the Growth of Paired Ugandan Isolates of Mycobacterium tuberculosis within Human Mononuclear Phagocytes Correlate with Epidemiological Evidence of Strain Virulence{triangledown}

Sue A. Theus,1 M. Donald Cave,1 Kathleen Eisenach,1 Jessica Walrath,2,3 Hung Lee,2,3 Wilma Mackay,2 Christopher Whalen,2 and Richard F. Silver2,3,4*

University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas,1 Case Western Reserve University School of Medicine,2 Louis Stokes Cleveland Veterans' Affairs Medical Center,3 University Hospitals of Cleveland, Cleveland, Ohio4

Received 5 April 2006/ Returned for modification 12 June 2006/ Accepted 6 September 2006

Previous studies have suggested that isolates of Mycobacterium tuberculosis responsible for tuberculosis outbreaks grow more rapidly within human mononuclear phagocytes than do other isolates. Clinical scenarios suggesting virulence of specific M. tuberculosis isolates are readily identified. Determination of appropriate "control" isolates for these studies is more problematic, but equally important for validating these assays and, ultimately, for identifying biologic differences between M. tuberculosis strains that contribute to virulence. We utilized the database from a study of Ugandan tuberculosis patients and their household (HH) contacts to identify M. tuberculosis isolates transmitted within HH and nontransmitted control isolates. Isolate pairs were evaluated from matched HH in each of three clinical scenarios: (i) coprevalent disease and no disease, (ii) incident disease and no disease, and (iii) M. tuberculosis infection (purified protein derivative [PPD] positive) and no infection (PPD negative). Intracellular growth of paired organisms was determined in a blinded fashion using two models of intracellular infection in which we have previously demonstrated correlation between intracellular growth and strain virulence, primary human monocytes (MN) and THP-1 human macrophage-like cells. In both models, transmitted isolates from coprevalent disease HH displayed more rapid growth than nontransmitted control isolates. In the THP-1 model, this was also true of transmitted isolates from HH with incident disease and their controls. Differences in production of tumor necrosis factor alpha and interleukin-10 by matched isolates showed correlation with growth patterns in the THP-1 cells but not in MN. Paired isolates characterized in this manner may be of particular interest for further investigations of the virulence of M. tuberculosis.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, Biomedical Research Building, Rm. 1030, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44122. Phone: (216) 368-1151. Fax: (216) 368-2034. E-mail: rfs4{at}po.cwru.edu.

{triangledown} Published ahead of print on 18 September 2006.

Editor: F. C. Fang

Infection and Immunity, December 2006, p. 6865-6876, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00561-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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