Differences in the Growth of Paired Ugandan Isolates ofMycobacterium tuberculosiswithin Human Mononuclear Phagocytes Correlate with Epidemiological Evidence of Strain Virulence

Abstract

Previous studies have suggested that isolates ofMycobacterium tuberculosisresponsible for tuberculosis outbreaks grow more rapidly within human mononuclear phagocytes than do other isolates. Clinical scenarios suggesting virulence of specificM. tuberculosisisolates 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 betweenM. tuberculosisstrains that contribute to virulence. We utilized the database from a study of Ugandan tuberculosis patients and their household (HH) contacts to identifyM. tuberculosisisolates 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. tuberculosisinfection (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 ofM. tuberculosis.