Mycobacterium tuberculosis: success through dormancy

Abstract

Tuberculosis (TB) remains a major health threat, killing nearly 2 million individuals around this globe, annually. The only vaccine, developed almost a century ago, provides limited protection only during childhood. After decades without the introduction of new antibiotics, several candidates are currently undergoing clinical investigation. Curing TB requires prolonged combination of chemotherapy with several drugs. Moreover, monitoring the success of therapy is questionable owing to the lack of reliable biomarkers. To substantially improve the situation, a detailed understanding of the cross-talk between human host and the pathogen Mycobacterium tuberculosis (Mtb) is vital. Principally, the enormous success of Mtb is based on three capacities: first, reprogramming of macrophages after primary infection/phagocytosis to prevent its own destruction; second, initiating the formation of well-organized granulomas, comprising different immune cells to create a confined environment for the host-pathogen standoff; third, the capability to shut down its own central metabolism, terminate replication, and thereby transit into a stage of dormancy rendering itself extremely resistant to host defense and drug treatment. Here, we review the molecular mechanisms underlying these processes, draw conclusions in a working model of mycobacterial dormancy, and highlight gaps in our understanding to be addressed in future research.

Figure 1. Transmission and pathology of tuberculosis (TB)

Transmission of TB between individuals occurs via aerosols of infectious bacilli. An estimated 50 million infections per year maintain a pool of ~2 billion latently infected individuals. In a few cases, infection directly transforms to active TB. Together with reactivation and reinfection this gives rise to approximately 9 million new TB cases annually. Upon inhalation of such droplets the pathogen reaches lung airways and is phagocytosed by alveolar macrophages. The infected host cell induces a localized proinflamatory response that attracts mononuclear cells and T lymphocytes to build up a granuloma, the hallmark tissue reaction of TB. Healthy individuals can control the pathogen at this stage but remain latently infected and thus at risk of reactivation lifelong. Granuloma maturation (solid, necrotic, caseous) occurs at different velocities and typically culminates in coexistence of all lesion forms during active TB. The caseating granuloma loses solidity due to decay of its center into a structureless accumulation of host cell debris, the caseum. Mycobacterium tuberculosis (Mtb) grows to high numbers, is released into airways and coughed out as contagious aerosol.

Figure 2. Metabolic pathways of Mtb important during infection

Growing evidence suggests that pathogenic mycobacteria rely on lipids in vivo. Degradation of fatty acids by β-oxidation leads to acetyl-CoA (C₂) and for uneven chain length or methyl-branched fatty acids additionally to propionyl-CoA (C₃). The pathogen can directly metabolize C₂ units via the tricarboxcylic acid (TCA) cycle while excessive accumulation of toxic propionyl-CoA is prevented by two metabolic routes: (1) the methylcitrate cycle and (2) the methylmalonyl pathway. The products of both pathways can enter the TCA cycle, either directly (succinate) or after conversion to succinyl-CoA (methylmalonyl-CoA). Moreover, methylmalonyl-CoA is a building block of methyl-branched lipids. Mycobacterial isocitrate lyase (Icl) plays a key role in the methylcitrate cycle and the glyoxylate shunt. The intermediate glyoxylate can be used terminally to generate pyruvate (via malate), from which glycolytic substrates can be replenished by gluconeogenesis. C₃ bodies of the glycolysis/gluconeogenesis and acetyl-CoA are required for biosynthesis of triacylglycerol, a lipid relevant during dormancy.

Figure 3. Dynamic model of latent tuberculosis infection (LTBI) and active tuberculosis

In this model, LTBI is characterized by predominance of dormant bacilli and only very few active scouts capable of sensing the environment for growth attractiveness, which is low inside the solid granuloma. Some Mtb wake-up stochastically to maintain a small pool of scouts (left panel). Once the environment provides more favorable conditions, for example, in a caseating granuloma, scouts resuscitate dormant bacilli to become active probably by secretion of resuscitation promoting factors (Rpfs) (right panel). A few organisms remain dormant and therefore phenotypically drug-resistant, explaining the long treatment time required to cure active TB.