Tuberculosis (TB) is a highly complex and variable disease that presents along a spectrum of infection outcomes.
The TB granuloma is a primary contributor to the biological heterogeneity of TB.
Local inflammation, the immune response and bacterial state all contribute to the outcome of a granuloma, and thus there are multiple pathways by which to either achieve control or promote dissemination.
The failure of one or a few granulomas is sufficient to initiate disease progression and influence the clinical status of the host.
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.
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The authors gratefully acknowledge the intellectual contributions of the members of the Flynn and Fortune laboratories, as well as P. Ling Lin, E. Klein, J. Mattila and C. Scanga for helpful discussions. This work was supported, in part, by the US National Institutes of Health (T32 AI089443 to A.M.C.; AI094745, HL110811, AI105422 and AI123093 to J.L.F.; and AI114674 to J.L.F. and S.M.F.), the Bill and Melinda Gates Foundation (to J.L.F. and S.M.F.) and the Aeras Global Fund (to J.L.F. and S.M.F.). Support was also provided by the Burroughs Wellcome Foundation (to S.M.F.).
The authors declare no competing financial interests.
- Tuberculin skin test
A test that involves the induction of a delayed-type hypersensitivity reaction by an intradermal injection of purified protein derivative, which is a mixture of Mycobacterium tuberculosis-derived proteins. The tuberculin skin test is also known as the Mantoux test and is used as a diagnostic tool for M. tuberculosis infection, but it does not distinguish latent infection from active tuberculosis.
- Acid-fast staining
A method for staining mycobacteria for microscopic visualization, as the Gram stain is not useful for mycobacteria. Acid-fast staining relies on phenolic compounds that interact with the lipid-rich cell walls of mycobacteria, and the resistance of this interaction to acid alcohol is the basis of the term 'acid-fast'.
- Positron emission tomography
An imaging method that depends on the 3D detection of radiation (positrons) from a probe that is typically localized by uptake and retention in a specific cell or by a specific process in vivo. This uptake provides functional information about the organ of interest.
- Computed tomography
An imaging method that uses computer-processed combinations of many X-ray images taken from different angles to produce cross-sectional (tomographic) images (virtual 'slices') of specific areas of a scanned object, resulting in a 3D representation of an organ in a living subject. This provides structural information about the organ of interest.
- Pulmonary cavitation
The formation of a cavity in the lung. A cavity is an abnormal, gas-filled space with a lining wall that has developed within and replaced the normal lung architecture. In tuberculous disease, these cavities are formed when necrosis invades through the wall of an airway, dilating and distorting the structure, and leading to the discharge of necrotic debris into the bronchial tree.
- Ghon complex
A term for pathological lesions in latent tuberculosis infection that consist of an often-calcified granuloma and an associated lymph node.
- Molecular distance to health
A numerical score that measures the global transcriptional difference of each patient relative to the median in healthy controls.
A hallmark feature of human tuberculous granulomas that results from a distinctive type of central necrotic breakdown known as caseous necrosis. The term caseum derives from the 'cheese-like' appearance of the necrotic area.
Pathological processes by which the pulmonary infiltration of cells, fluid or other material leads to the loss of aeration and of the normal spongy consistency, causing parenchymal tissue to have a more firm, solid texture. Such a change is most commonly associated with infection-induced inflammatory infiltrates and leads to pneumonia.
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Cadena, A., Fortune, S. & Flynn, J. Heterogeneity in tuberculosis. Nat Rev Immunol 17, 691–702 (2017). https://doi.org/10.1038/nri.2017.69
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