The spectrum of latent tuberculosis: rethinking the biology and intervention strategies

Abstract

Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.

Figure 1. TB infection as a spectrum

The outcome of infection by M. tuberculosis is generally represented as a bimodal distribution between active TB and latent TB on the basis of the presence or absence of clinical symptoms. We propose that latent TB is more usefully represented as part of a spectrum of responses to infection. One consequence of this model is that there may be a subpopulation within the group currently defined as having latent TB who should be preferentially targeted for preventive therapy. A second consequence is that efforts to develop drugs for effective treatment of latent TB would overlap the search for drugs that would shorten treatment times for active TB.

Figure 2. PET/CT imaging

An [¹⁸F]-FDG-PET-CT scan of a human tuberculosis patient with extensive bilateral disease and a complete collapse of the left lung. The right lung also shows extensive disease throughout and illustrates the variability of FDG-PET uptake amongst lesions within even a single infected patient. The yellow star illustrates one lesion that fails to take up FDG that lies immediately adjacent to a string of three lesions that take up label avidly (red star). These different types of lesions respond with very different kinetics to chemotherapy suggesting they represent distinct bacterial subpopulations in different microenvironments.

Figure 3. Tuberculous granulomas

There are several granuloma types that can be found among humans and non-human primates, even within the same individual. A. The classic tuberculous granuloma, found in active disease and latent infection, is the caseous granuloma, composed of epithelioid macrophages, neutrophils, a cuff of lymphocytes (CD4 and CD8 T cells, B cells) and sometimes surrounded by peripheral fibrosis. The center of this type of granuloma is caseous, a necrotic state that likely consists of dead macrophages and other cells. This area is hypoxic. Mycobacteria in this granuloma could be found in macrophages (either in contact with T cells or not) or in the hypoxic center, or possibly even in the fibrotic rim, leading to different microenvironments for the bacteria. B. The non-necrotizing granuloma is usually seen in active disease, and consists primarily of macrophages with some lymphocytes; this lesion can be seen in guinea pigs and mice, albeit with more lymphocytes. M. tuberculosis bacilli are within macrophages in this lesion. C. Fibrotic lesions are seen mostly in latent tuberculosis but also in active disease, and are composed almost completely of fibroblasts, with a minimal number of macrophages. Although it is possible to culture bacilli from some fibrotic lesions, it is not clear where the bacilli reside, perhaps in macrophages or in the fibrotic area, or what the microenvironment is like.

Figure 4. A systems approach to the pathology of tuberculosis

Progress in understanding the complex biology of human tuberculosis – and applying this knowledge to drug development – will depend on being able to integrate multiple sources of data into in silico models that allow us to prioritise experiments and predict effective interventions.

Figure 5. A lesion-based framework for study of latent TB and drug development

Latent and active TB in humans and non-human primates comprises a heterogeneous mixture of lesions that generate a range of physiological microenvironments associated with bacterial replication, persistence and killing. Characterisation of the different types of lesion using state-of-the-art imaging, cellular and molecular techniques will provide a framework for understanding the biology of TB and for the development of drugs targeted against relevant bacterial subpopulations.