The remarkable ability of Mycobacterium tuberculosis to survive attacks from the host immune response and drug treatment is due to the resilience of a few bacilli rather than a result of survival of the entire population. Maintenance of mycobacterial subpopulations with distinct phenotypic characteristics is key for survival in the face of dynamic and variable stressors encountered during infection. Mycobacterial populations develop a wide range of phenotypes through an innate asymmetric growth pattern and adaptation to fluctuating microenvironments during infection that point to heterogeneity being a vital survival strategy. In this Review, we describe different types of mycobacterial heterogeneity and discuss how heterogeneity is generated and regulated in response to environmental cues. We discuss how this heterogeneity may have a key role in recording memory of their environment at both the single-cell level and the population level to give mycobacterial populations plasticity to withstand complex stressors.
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Work in B.B.A.’s laboratory was funded, in part, by the Bill and Melinda Gates Foundation (OPP1204444) and the NIH (R01 AI143611-01).
The authors declare no competing interests.
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Complex lesion structures that form during tuberculosis pathogenesis and consist of immune cells, epithelioid cells and necrotic tissue.
- Macrophage activation
A change in physiology in response to signals from adaptive or innate immune mechanisms that enable macrophages to perform specialized effector functions.
- Necrotic caseum
Lipid-rich environment within granulomas derived primarily from necrotic cellular debris.
Protein complex responsible for performing membrane division and cell wall division functions.
- Accelerator cell
A cell that inherits the pole from which its mother cell grew and usually elongates at a higher rate than alternator cells.
- Alternator cell
A cell that generates a new growth pole upon birth and elongates at a lower rate than accelerator cells.
Lipids of a type present on the outer leaflet mycobacterial envelope that influence biofilm formation, growth and pathogenicity.
- Isogenic sister cells
Cells born from the same mother and that share identical genotypes.
- Minimum inhibitory concentration
The lowest concentration of a drug that will inhibit growth.
- Collaborative crosses
Panels of mouse strains with significant genomic variation designed to mimic the heterogeneity of the human population and its spectrum of disease phenotypes.
- Foamy macrophages
Macrophages that are abundant in intracellular lipid droplets formed from pathogen-induced perturbation of lipid biosynthesis.
- Virulence factors
Components of a pathogen that enable it to invade and colonize a host.
- Secretion systems
Molecular nanomachines present on the outer surface of a pathogen that secrete substrates to promote pathogenicity.
- Antimicrobial breakpoints
The lowest concentration of a drug that will inhibit the growth of almost all wild type strains (95%) of the organism but does not inhibit clinical strains that are resistant.
The relationship between drug distribution, absorption, metabolism and concentration in the human body over time.
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Chung, E.S., Johnson, W.C. & Aldridge, B.B. Types and functions of heterogeneity in mycobacteria. Nat Rev Microbiol 20, 529–541 (2022). https://doi.org/10.1038/s41579-022-00721-0