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Chapter 32 : Phenotypic Heterogeneity in

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Abstract:

The terms “genotype” and “phenotype” were coined by the botanist and geneticist Wilhelm Johannsen at the beginning of the 20th century ( ). Both words have a Greek etymology, meaning “generation of form” and “appearance of form,” respectively. Hierarchically, the genotype predates the phenotype, considering that the genotype is defined as the genetic composition of a living entity, while the phenotype is defined as the perceivable characteristics of a living entity, which result from the interaction between the genetic composition and the environment. From unicellular to multicellular organisms, from bacteria to animals, the key for success, especially to evolve and adapt, lies in diversity. Diversity offers two main advantages: first, variants, exhibiting variety, could have a potential advantage against rapid adverse changes in environment, and, second, variants could potentially interact among themselves (mutualism) and perform more efficiently as a population than as individuals. Therefore, organisms have developed various means of generating and maintaining diversity. Changing the genetic content is a way of generating this diversity even though such changes are less frequent and can potentially be detrimental unless selected. Regardless, genetic diversity has been extensively documented even in monomorphic organisms such as , and this often has a significant impact on the host-pathogen interaction and stimulation of host immune responses ( ) as well as treatment outcomes ( ). For example, some pathogens exhibit phase variation whereby diversity is generated by highly mutable loci ( ). Genetic diversity in is being reviewed elsewhere ( ) and will not be addressed here. In this review we focus exclusively on nongenetic modes of heterogeneity.

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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Figure 1

Causes and consequences of phenotypic heterogeneity. Bacterial isogenic populations arising from a single progenitor cell are usually expected to be homogeneous (left snapshot). However, single-cell analysis unveils significant cell-to-cell heterogeneity (right snapshot). Some of the causal factors leading to this heterogeneity are variations in growth rate, growth continuity, interdivision time, division symmetry, gene expression, protein distribution, and cell age generated either through deterministic or stochastic mechanisms.

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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Figure 2

Stress conditions enhance phenotypic heterogeneity. Upper panel, single-cell rRNA-GFP fluorescence of isolated from different environments: Exp (exponential phase), Stat (stationary phase), Drug (treated with isoniazid), Mɸ (grown in macrophages), and Mouse (explanted from mouse lungs during the acute phase of infection). Each circle represents a single cell and the mean fluorescence ± SD is indicated (n = 200 per time point). Asterisks indicate significance difference of each data set in comparison with the control group, Exp ( < 0.0001), according to ANOVA followed by the Kruskal-Wallis test. The numbers shown on top are the coefficient of variation (CV) for each data set. Lower panel, representative snapshots from the corresponding conditions are shown. Green (rRNA-GFP) and red (constitutive dsRed) fluorescence channels are merged. Macrophages are also shown in phase contrast. Scale bars, 5 μm. Figure adapted from Manina et al. ( ).

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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Figure 3

Identification of NGMA bacteria by single-cell techniques. A schematic of the fluorescence recovery after photobleaching (FRAP) method is shown on the top. expressing cytoplasmic rRNA-GFP were subjected to photobleaching using a laser, followed by staining with a dye that penetrates only cells with a compromised membrane. Metabolically active cells (green), bleached or metabolically inactive cells (gray), and dead cells (blue) are depicted. Representative snapshots of stationary-phase cells that were exposed to fresh 7H9 medium for 1 week. Top row, a nongrowing cell that does not recover fluorescence after photobleaching and stains positive for dead-cell stain (negative control). Middle row, a nongrowing cell that recovers fluorescence after photobleaching and stains negative for dead-cell stain and is therefore identified as nongrowing but metabolically active (NGMA). Bottom row, a growing cell that recovers fluorescence after photobleaching, stains negative for dead-cell stain, and continues to grow postbleaching.

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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Figure 4

Host and pathogen heterogeneity contributes to TB diversity. Schematic of the increasingly heterogeneous environments resides in. Disease heterogeneity initiates in the major site of infection where host immunity gives rise to the typical granulomatous lesion (magnified from the lung parenchyma). This assembly of host cells consists of different types of macrophages, dendritic cells, neutrophils, lymphocytes, fibroblasts, and a necrotic caseous core. Bacilli can reside in discrete niches both intracellularly (magnified from the granuloma) and extracellularly, where they are subjected to a plethora of host immune effectors (red arrow) and antibiotics (blue arrow). Diverse environmental cues found within each microniche contribute to enhance the intrinsic phenotypic diversity of (right snapshot).

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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Figure 5

Cellular dynamic processes and single-cell techniques. The different biological processes that occur during cell growth and that often determine cell fate and some of the techniques that are used to track these processes at the single-cell level are depicted. Fluorescent approaches involve the use of fluorescent protein fusions or fluorescent-tagged molecules. Figure adapted from Spiller et al. ( ).

Citation: Dhar N, McKinney J, Manina G. 2017. Phenotypic Heterogeneity in , p 671-697. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0021-2016
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