Heterogeneity in tuberculosis

Abstract

Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.

Figure 1 |. A classical tuberculosis granuloma.

The hallmark tuberculosis granuloma is a highly organized collection of immune cells that aggregate around a central necrotic core. Reproduced from REF. © Macmillan Publishers Limited. NK, natural killer.

Figure 2 |. Granuloma fate is influenced by a complex and dynamic exchange of host and bacterial features.

In the lungs, a crucial interplay between the bacteria and host immune cells influences inflammatory programmes that contribute to granuloma outcome. This process is highly dynamic and iterative, with multiple components having pleiotropic, knock-on and feedback effects on inflammation and the host–pathogen interaction.

Figure 3 |. Multiple ‘equations’ can determine granuloma fate.

There are multiple pathways that lead to both resolved and unresolved granuloma outcomes in human tuberculosis. These are fluid and dynamic processes that change as the structures encounter different contexts of immune responses, inflammation and bacterial persistence.

Figure 4 |. Individual granulomas establish variable host outcomes and contribute to the overall spectrum of tuberculosis.

a | An individual cynomolgus macaque in which all granulomas have resolved, thus leading to an asymptomatic, contained outcome, has the lowest risk of reactivation of infection, and has effectively cleared most or all of the Mycobacterium tuberculosis infection. b | An individual macaque that has one or more granulomas that contain viable M. tuberculosis but can be asymptomatic for clinical tuberculosis (TB). These granulomas are not actively disseminating or progressing to worse pathologies, but they may have a persistent low level of inflammation. c | An individual macaque that has one or more very poorly controlled granulomas that are actively disseminating bacteria to other sites (indicated by outward-pointing arrows) can develop progressive disease and potentially worse forms of active TB.