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

Abstract

Latent tuberculosis is defined by the presence of an antigen-specific T cell response in the absence of clinical symptoms. It includes conditions ranging from clearance of the pathogen, maintenance of quiescent infected foci to active subclinical disease, and can be viewed as part of a spectrum of outcomes to infection with Mycobacterium tuberculosis. The pathogenesis of tuberculosis depends on localized granulomatous responses. Different types of granuloma can promote bacterial killing, persistence or replication. Live imaging by positron emission tomography and computed tomography in humans and non-human primates provides powerful new opportunities to analyse tuberculosis lesions in terms of spatial distribution and dynamic behaviour in the presence and absence of drugs. Different granulomas provide different microenvironments that can support heterogeneous subpopulations of bacteria differing in phenotypic adaptation and drug susceptibility. Systems biology approaches will be important in the molecular characterization of the microenvironment within lesions and the corresponding bacterial physiology. Drug strategies based on simple inhibition of individual enzyme targets have proved largely ineffective for the discovery of novel antimicrobials. An improved understanding of actual bactericidal mechanisms will be important in rational targeting of new drugs against persistent bacterial phenotypes. In addition to the development of drugs that are customized against different subpopulations of bacteria, the use of preventive therapy as an intervention for the control of global tuberculosis will benefit from further definition of the spectrum of latent disease. Imaging profiles and biomarkers will assist in clinical trials of new drugs and in the identification of individuals at highest risk disease progression.