Review
M. tuberculosis persistence, latency, and drug tolerance

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Abstract

The success of Mycobacterium tuberculosis as a pathogen is largely attributable to its ability to persist in host tissues, where drugs that are rapidly bactericidal in vitro require prolonged administration to achieve comparable effects. Latency is a frequent outcome of untreated or incompletely treated M. tuberculosis infection, creating a long-standing reservoir of future disease and contagion. Although the interactions between the bacterium and its host that result in chronic or latent infection are still largely undefined, recent years have seen a resurgence of interest and research activity in this area. Here we review some of the classic studies that have led to our current understanding of M. tuberculosis persistence, and discuss the varied approaches that are now being brought to bear on this important problem.

Introduction

The invention of antimicrobial chemotherapy in the 20th century was a watershed event in the history of medicine. Thanks to the new “magic bullets”, many of the most common and deadly infections that had ravaged the US and Europe for centuries became minor and treatable ailments. The first antimicrobials proved ineffective against tuberculosis (TB), the “Great White Plague” that was responsible for more killing more young adults each year than any other infection. The search for a cure finally culminated, in the mid-1940s, in the discovery of streptomycin by Schatz and Waksman and of para-amino salicylate (PAS) by Lehmann. When the more effective drugs isoniazid (INH) and pyrazinamide (PZA) were introduced in the early 1950s, TB became a treatable disease. As predicted by Ehrlich,2 combination therapy with multiple drugs was widely adopted once it was found that “under the influence of two different medicines the danger of rendering the parasites immune, which naturally would be a very great obstacle in connection with further treatment, is apparently greatly minimized.” In his optimistically entitled book “The Conquest of Tuberculosis”, Waksman went so far as to predict that “the ancient foe of man, known as consumption, the great white plague, tuberculosis, or by whatever other name, is on the way to being reduced to a minor ailment of man. The future appears bright indeed, and the complete eradication of the disease is in sight.”3

Forty years later, and despite half a century of anti-TB chemotherapy, there are still 8–10 million new cases of active TB each year, and nearly 2 billion individuals are believed to harbor latent TB based on tuberculin skin test (TST) surveys.4 Why has this treatable bacterial infection failed to yield to modern medicine? While the full answer to this question is complex, one issue seems clear: the features that enable M. tuberculosis to persist within the tissues of its host have also allowed TB to remain one of the world's great killers into the 21st century. This problem was anticipated by Ehrlich2 in 1913, in an historic address at the dawn of the chemotherapy era: “Now that the liability to, and danger of, disease are to a great extent circumscribed … the efforts of chemotherapeutics are directed as far as possible to fill up the gaps left in this ring, more especially to bring healing to diseases in which the natural powers of the organism are insufficient”. Ninety years later, the ring has not yet been closed in the case of TB, where the “natural powers” of the human immune system are clearly “insufficient” to resolve infection.

Section snippets

Latency, dormancy, and persistence

Three terms, latency, persistence, and dormancy, are commonly used in describing M. tuberculosis and TB pathogenesis. Because these terms have not always been used consistently in the literature, they will be defined here as they will be used in this review, with our apologies to those whose ideas differ. Latency was defined by Amberson5 as “the presence of any tuberculous lesion which fails to produce symptoms of its presence”. Latency can be achieved through either the early restriction of M.

Persistence ex vivo

Long before the discovery of streptomycin and other antimicrobials, M. tuberculosis was known to be an unusually hardy bacterium, both inside and outside the body. In the early 20th century, researchers subjected M. tuberculosis to a barrage of environmental assaults to ascertain which conditions affected the organism's viability and virulence (8 and references therein). M. tuberculosis proved quite adept at withstanding a wide variety of ex vivo insults, including desiccation, nutrient

Latency

Prior to the antibiotic era, TB was considered a lifelong infection: “Once tuberculous, always tuberculous”. This clinical adage was recently given a new twist by a molecular epidemiology study in Denmark, which provided the first compelling molecular evidence for the existence of extraordinarily long periods of latency in untreated humans.10 This study examined the case of a Danish man who first developed TB in 1990. When the IS6110 fingerprint of the M. tuberculosis strain isolated from this

Drug tolerance

If the fate of bacilli in naturally healed lesions continues to be controversial, the status of tubercle bacilli within patients treated with antimicrobials is even less clear. Following the introduction of TB chemotherapy in the late 1940s, surgical resection of tuberculous lesions became increasingly common and provided material for numerous bacteriological studies. Several reports published in the mid-1950s showed that large numbers of acid-fast bacilli could be observed by microscopy in

Modeling persistence in vitro

The simplest model of M. tuberculosis persistence is the stationary phase culture. The kinetics of replication of M. tuberculosis in the lungs of mice are reminiscent of the organism's replication kinetics in culture: an initial period of exponential growth is followed by an extended period during which the number of viable bacilli remains stable. Admittedly, the forces that bring about the cessation of growth in vitro (nutrient exhaustion) are not equivalent to those in vivo (acquired

Modeling persistence in animals

The phenomenon of latency has been difficult to reproduce in a tractable small animal model. Apart from non-human primates,57 which are prohibitively expensive and impractical for general use, rabbits provide the closest facsimile of human tuberculosis in terms of tissue pathology and disease progression. Half a century ago, Lurie bred resistant and susceptible strains of rabbits, and demonstrated that the differential outcome of TB infections in these strains was determined by early events

Recent progress

During the past decade, the development of molecular-genetic tools for the analysis of M. tuberculosis has significantly advanced our ability to study the in vivo biology of M. tuberculosis.83 Genetic and gene expression-based studies have led to the identification of genes that appear to be involved in the adaptation of M. tuberculosis to life in the lungs. The mouse continues to be the most frequently used model for studies of M. tuberculosis pathogenesis, although there has been a renewal of

What next?

During the past decade, there has been a resurgence of interest in the phenomenon of M. tuberculosis persistence. In the United States, this has been due in part to the recognition that the demographics of TB are shifting.95 In 1990, three-quarters of all TB cases in the United States were among the US-born; a decade later, the numbers of cases among the US-born and foreign-born were roughly equal. Most significantly, from 1990 to 2000, there was a marked fall in the absolute number of TB cases

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