Early clearance of Mycobacterium tuberculosis: a new frontier in prevention

Abstract

Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for EC comes from case contact studies that consistently show that a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, natural killer T cells, mucosa-associated invariant T cells and cd T cells may assist. How EC may be impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection.

Figure 1

Phenotypes in the progression to tuberculosis (TB) disease after exposure. Mycobacterium tuberculosis (Mtb) exposure leads to infection. Early clearance (EC) occurs before the development of an adaptive immune response and is likely to be due to innate factors, during Stage I or II. If the pathogen evades EC mechanisms, an adaptive response develops (Stage III), measurable through a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). Early evasion of both innate and adaptive responses results in primary progressive TB. However, in the majority of infected individuals M. tuberculosis is contained as latent TB infection with only 5% later reactivating disease. Others speculate that clearance could also occur at the time of or after TST/IGRA conversion, we term this delayed clearance.

Figure 2

Hypothesized mechanisms of clearance versus infection during first and second stages of Mycobacterium tuberculosis (Mtb) infection. In stage one infection is primarily of alveolar macrophages. Activation of macrophages may be important for early clearance (EC), through recognition of M. tuberculosis via surface, cytosolic or phagosomal pattern recognition receptors (PRRs) and/or tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) secreted by other cells. This promotes killing of intracellular M. tuberculosis by phagosomal acidification, hydrolytic enzymes and generation of reactive nitrogen intermediates. Also, antimicrobial peptides and autophagy promote mycobacterial killing and are both induced by vitamin D. Alternatively, infection is favoured if the macrophage's initial interaction with M. tuberculosis is via ligation of the mannose receptor (MR). This promotes uptake without recognition and inhibition of phagolysosomal fusion. In stage two, infected macrophages undergo apoptosis and express adenosine triphosphate and phosphotidyl serine. This attracts monocytes and neutrophils that engulf the infected cell and deploy oxidative killing mechanisms to achieve clearance. Neutrophils activated in this fashion secrete antimicrobial peptides cathelicidin, human neutrophil peptides and Lipocalin 2 to kill infected monocytes. Sustained infection is most likely when infected macrophages undergo necrotic cell death. The disruption of the macrophage membrane facilitates mycobacterial outgrowth so newly recruited monocytes are infected and logarithmic growth ensues. IL-1β, interleukin-1β; MAIT, mucosa-associated invariant T; NK-T, natural killer T; PMN, polymorphonuclear cells; PS, phosphatidyl serine; TLR, Toll-like receptor