Chapter 32 : Phenotypic Heterogeneity in

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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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1. Johannsen W . 1911. The genotype conception of heredity. Am Nat 45 : 129 159. [CrossRef] [CrossRef]
2. Warner DF,, Koch A,, Mizrahi V . 2015. Diversity and disease pathogenesis in Mycobacterium tuberculosis . Trends Microbiol 23 : 14 21. [CrossRef] [CrossRef]
3. Coscolla M,, Gagneux S . 2014. Consequences of genomic diversity in Mycobacterium tuberculosis . Semin Immunol 26 : 431 444. [CrossRef] [CrossRef]
4. Reed MB,, Domenech P,, Manca C,, Su H,, Barczak AK,, Kreiswirth BN,, Kaplan G,, Barry CE III . 2004. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431 : 84 87. [CrossRef] [CrossRef]
5. Barczak AK,, Domenech P,, Boshoff HIM,, Reed MB,, Manca C,, Kaplan G,, Barry CE III . 2005. In vivo phenotypic dominance in mouse mixed infections with Mycobacterium tuberculosis clinical isolates. J Infect Dis 192 : 600 606. [CrossRef] [CrossRef]
6. Liu Q,, Via LE,, Luo T,, Liang L,, Liu X,, Wu S,, Shen Q,, Wei W,, Ruan X,, Yuan X,, Zhang G,, Barry CE III,, Gao Q . 2015. Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment. Sci Rep 5 : 17507. [CrossRef] [CrossRef]
7. Bayliss CD . 2009. Determinants of phase variation rate and the fitness implications of differing rates for bacterial pathogens and commensals. FEMS Microbiol Rev 33 : 504 520. [CrossRef] [CrossRef]
8. Beaumont HJ,, Gallie J,, Kost C,, Ferguson GC,, Rainey PB . 2009. Experimental evolution of bet hedging. Nature 462 : 90 93. [CrossRef] [CrossRef]
9. Veening J-W,, Smits WK,, Kuipers OP . 2008. Bistability, epigenetics, and bet-hedging in bacteria. Annu Rev Microbiol 62 : 193 210. [CrossRef] [CrossRef]
10. Sureka K,, Ghosh B,, Dasgupta A,, Basu J,, Kundu M,, Bose I . 2008. Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PLoS ONE 3 : e1771.[CrossRef]
11. Elowitz MB,, Levine AJ,, Siggia ED,, Swain PS . 2002. Stochastic gene expression in a single cell. Science 297 : 1183 1186. [CrossRef] [CrossRef]
12. Wakamoto Y,, Dhar N,, Chait R,, Schneider K,, Signorino-Gelo F,, Leibler S,, McKinney JD . 2013. Dynamic persistence of antibiotic-stressed mycobacteria. Science 339 : 91 95. [CrossRef] [CrossRef]
13. Lindsey HA,, Gallie J,, Taylor S,, Kerr B . 2013. Evolutionary rescue from extinction is contingent on a lower rate of environmental change. Nature 494 : 463 467. [CrossRef] [CrossRef]
14. Sánchez-Romero MA,, Casadesús J . 2014. Contribution of phenotypic heterogeneity to adaptive antibiotic resistance. Proc Natl Acad Sci USA 111 : 355 360. [CrossRef] [CrossRef]
15. Draghi JA,, Parsons TL,, Wagner GP,, Plotkin JB . 2010. Mutational robustness can facilitate adaptation. Nature 463 : 353 355. [CrossRef] [CrossRef]
16. Bjedov I,, Tenaillon O,, Gérard B,, Souza V,, Denamur E,, Radman M,, Taddei F,, Matic I . 2003. Stress-induced mutagenesis in bacteria. Science 300 : 1404 1409. [CrossRef] [CrossRef]
17. Rosenberg SM . 2001. Evolving responsively: adaptive mutation. Nat Rev Genet 2 : 504 515. [CrossRef] [CrossRef]
18. McGrath M,, Gey van Pittius NC,, van Helden PD,, Warren RM,, Warner DF . 2014. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis . J Antimicrob Chemother 69 : 292 302. [CrossRef] [CrossRef]
19. Hendrickson H,, Slechta ES,, Bergthorsson U,, Andersson DI,, Roth JR . 2002. Amplification-mutagenesis: evidence that “directed” adaptive mutation and general hypermutability result from growth with a selected gene amplification. Proc Natl Acad Sci USA 99 : 2164 2169. [CrossRef] [CrossRef]
20. Cui L,, Neoh H-M,, Iwamoto A,, Hiramatsu K . 2012. Coordinated phenotype switching with large-scale chromosome flip-flop inversion observed in bacteria. Proc Natl Acad Sci USA 109 : E1647 E1656. [CrossRef] [CrossRef]
21. Dubnau D,, Losick R . 2006. Bistability in bacteria. Mol Microbiol 61 : 564 572. [CrossRef] [CrossRef]
22. van der Woude MW . 2011. Phase variation: how to create and coordinate population diversity. Curr Opin Microbiol 14 : 205 211. [CrossRef] [CrossRef]
23. Vega NM,, Allison KR,, Khalil AS,, Collins JJ . 2012. Signaling-mediated bacterial persister formation. Nat Chem Biol 8 : 431 433. [CrossRef] [CrossRef]
24. Abramovitch RB,, Rohde KH,, Hsu F-F,, Russell DG . 2011. aprABC: a Mycobacterium tuberculosis complex-specific locus that modulates pH-driven adaptation to the macrophage phagosome. Mol Microbiol 80 : 678 694. [CrossRef] [CrossRef]
25. Tan S,, Sukumar N,, Abramovitch RB,, Parish T,, Russell DG . 2013. Mycobacterium tuberculosis responds to chloride and pH as synergistic cues to the immune status of its host cell. PLoS Pathog 9 : e1003282.[CrossRef] [CrossRef]
26. Kærn M,, Elston TC,, Blake WJ,, Collins JJ . 2005. Stochasticity in gene expression: from theories to phenotypes. Nat Rev Genet 6 : 451 464. [CrossRef] [CrossRef]
27. Raj A,, van Oudenaarden A . 2008. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135 : 216 226. [CrossRef] [CrossRef]
28. Rando OJ,, Verstrepen KJ . 2007. Timescales of genetic and epigenetic inheritance. Cell 128 : 655 668. [CrossRef] [CrossRef]
29. Drake JW,, Charlesworth B,, Charlesworth D,, Crow JF . 1998. Rates of spontaneous mutation. Genetics 148 : 1667 1686.
30. Ford CB,, Lin PL,, Chase MR,, Shah RR,, Iartchouk O,, Galagan J,, Mohaideen N,, Ioerger TR,, Sacchettini JC,, Lipsitch M,, Flynn JL,, Fortune SM . 2011. Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet 43 : 482 486. [CrossRef] [CrossRef]
31. Eldar A,, Chary VK,, Xenopoulos P,, Fontes ME,, Losón OC,, Dworkin J,, Piggot PJ,, Elowitz MB . 2009. Partial penetrance facilitates developmental evolution in bacteria. Nature 460 : 510 514.[CrossRef]
32. Locke JC,, Young JW,, Fontes M,, Hernández Jiménez MJ,, Elowitz MB . 2011. Stochastic pulse regulation in bacterial stress response. Science 334 : 366 369. [CrossRef] [CrossRef]
33. Norman TM,, Lord ND,, Paulsson J,, Losick R . 2013. Memory and modularity in cell-fate decision making. Nature 503 : 481 486. [CrossRef] [CrossRef]
34. Rotem E,, Loinger A,, Ronin I,, Levin-Reisman I,, Gabay C,, Shoresh N,, Biham O,, Balaban NQ . 2010. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc Natl Acad Sci USA 107 : 12541 12546. [CrossRef] [CrossRef]
35. Manina G,, Dhar N,, McKinney JD . 2015. Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe 17 : 32 46. [CrossRef] [CrossRef]
36. Ackermann M . 2015. A functional perspective on phenotypic heterogeneity in microorganisms. Nat Rev Microbiol 13 : 497 508. [CrossRef] [CrossRef]
37. Casadevall A,, Pirofski LA . 2000. Host-pathogen interactions: basic concepts of microbial commensalism, colonization, infection, and disease. Infect Immun 68 : 6511 6518. [CrossRef] [CrossRef]
38. Gomez JE,, McKinney JD . 2004. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis (Edinb) 84 : 29 44. [CrossRef] [CrossRef]
39. Cambier CJ,, Takaki KK,, Larson RP,, Hernandez RE,, Tobin DM,, Urdahl KB,, Cosma CL,, Ramakrishnan L . 2014. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505 : 218 222. [CrossRef] [CrossRef]
40. Lenaerts A,, Barry CE III,, Dartois V . 2015. Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev 264 : 288 307. [CrossRef] [CrossRef]
41. Gideon HP,, Phuah J,, Myers AJ,, Bryson BD,, Rodgers MA,, Coleman MT,, Maiello P,, Rutledge T,, Marino S,, Fortune SM,, Kirschner DE,, Lin PL,, Flynn JL . 2015. Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization. PLoS Pathog 11 : e1004603. [CrossRef] [CrossRef]
42. Lin PL,, Ford CB,, Coleman MT,, Myers AJ,, Gawande R,, Ioerger T,, Sacchettini J,, Fortune SM,, Flynn JL . 2014. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 20 : 75 79. [CrossRef]
43. Coleman MT,, Chen RY,, Lee M,, Lin PL,, Dodd LE,, Maiello P,, Via LE,, Kim Y,, Marriner G,, Dartois V,, Scanga C,, Janssen C,, Wang J,, Klein E,, Cho SN,, Barry CE III,, Flynn JL . 2014. PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci Transl Med 6 : 265ra167.[CrossRef] [CrossRef]
44. Prideaux B,, Via LE,, Zimmerman MD,, Eum S,, Sarathy J,, O’Brien P,, Chen C,, Kaya F,, Weiner DM,, Chen P-Y,, Song T,, Lee M,, Shim TS,, Cho JS,, Kim W,, Cho S-N,, Olivier KN,, Barry CE III,, Dartois V . 2015. The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med 21 : 1223 1227. [CrossRef] [CrossRef]
45. Marakalala MJ,, Raju RM,, Sharma K,, Zhang YJ,, Eugenin EA,, Prideaux B,, Daudelin IB,, Chen PY,, Booty MG,, Kim JH,, Eum SY,, Via LE,, Behar SM,, Barry CE III,, Mann M,, Dartois V,, Rubin EJ . 2016. Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat Med 22 : 531 538. [CrossRef] [CrossRef]
46. Schwabe A,, Bruggeman FJ . 2014. Contributions of cell growth and biochemical reactions to nongenetic variability of cells. Biophys J 107 : 301 313. [CrossRef] [CrossRef]
47. Avery SV . 2006. Microbial cell individuality and the underlying sources of heterogeneity. Nat Rev Microbiol 4 : 577 587. [CrossRef] [CrossRef]
48. Eldar A,, Elowitz MB . 2010. Functional roles for noise in genetic circuits. Nature 467 : 167 173. [CrossRef] [CrossRef]
49. Ozbudak EM,, Thattai M,, Kurtser I,, Grossman AD,, van Oudenaarden A . 2002. Regulation of noise in the expression of a single gene. Nat Genet 31 : 69 73. [CrossRef] [CrossRef]
50. Choi PJ,, Cai L,, Frieda K,, Xie XS . 2008. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322 : 442 446. [CrossRef] [CrossRef]
51. Rosenfeld N,, Young JW,, Alon U,, Swain PS,, Elowitz MB . 2005. Gene regulation at the single-cell level. Science 307 : 1962 1965. [CrossRef] [CrossRef]
52. Golding I,, Paulsson J,, Zawilski SM,, Cox EC . 2005. Real-time kinetics of gene activity in individual bacteria. Cell 123 : 1025 1036. [CrossRef] [CrossRef]
53. Yu J,, Xiao J,, Ren X,, Lao K,, Xie XS . 2006. Probing gene expression in live cells, one protein molecule at a time. Science 311 : 1600 1603. [CrossRef] [CrossRef]
54. Cai L,, Friedman N,, Xie XS . 2006. Stochastic protein expression in individual cells at the single molecule level. Nature 440 : 358 362. [CrossRef] [CrossRef]
55. Alon U . 2007. Network motifs: theory and experimental approaches. Nat Rev Genet 8 : 450 461. [CrossRef] [CrossRef]
56. Smits WK,, Kuipers OP,, Veening J-W . 2006. Phenotypic variation in bacteria: the role of feedback regulation. Nat Rev Microbiol 4 : 259 271. [CrossRef] [CrossRef]
57. Ghosh S,, Sureka K,, Ghosh B,, Bose I,, Basu J,, Kundu M . 2011. Phenotypic heterogeneity in mycobacterial stringent response. BMC Syst Biol 5 : 18. [CrossRef] [CrossRef]
58. Tiwari A,, Balázsi G,, Gennaro ML,, Igoshin OA . 2010. The interplay of multiple feedback loops with post-translational kinetics results in bistability of mycobacterial stress response. Phys Biol 7 : 036005.[CrossRef] [CrossRef]
59. Taniguchi Y,, Choi PJ,, Li GW,, Chen H,, Babu M,, Hearn J,, Emili A,, Xie XS . 2010. Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329 : 533 538. [CrossRef] [CrossRef]
60. Rustad TR,, Minch KJ,, Brabant W,, Winkler JK,, Reiss DJ,, Baliga NS,, Sherman DR . 2013. Global analysis of mRNA stability in Mycobacterium tuberculosis . Nucleic Acids Res 41 : 509 517. [CrossRef] [CrossRef]
61. Schubert OT,, Mouritsen J,, Ludwig C,, Röst HL,, Rosenberger G,, Arthur PK,, Claassen M,, Campbell DS,, Sun Z,, Farrah T,, Gengenbacher M,, Maiolica A,, Kaufmann SHE,, Moritz RL,, Aebersold R . 2013. The Mtb proteome library: a resource of assays to quantify the complete proteome of Mycobacterium tuberculosis . Cell Host Microbe 13 : 602 612. [CrossRef] [CrossRef]
62. Silander OK,, Nikolic N,, Zaslaver A,, Bren A,, Kikoin I,, Alon U,, Ackermann M . 2012. A genome-wide analysis of promoter-mediated phenotypic noise in Escherichia coli . PLoS Genet 8 : e1002443 [CrossRef] [CrossRef]
63. Singh GP . 2013. Coupling between noise and plasticity in E. coli . G3 (Bethesda) 3 : 2115 2120. [CrossRef] [CrossRef]
64. Thieffry D,, Huerta AM,, Pérez-Rueda E,, Collado-Vides J . 1998. From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli . BioEssays 20 : 433 440. [CrossRef] [CrossRef]
65. Fraser HB,, Hirsh AE,, Giaever G,, Kumm J,, Eisen MB . 2004. Noise minimization in eukaryotic gene expression. PLoS Biol 2 : e137. [CrossRef] [CrossRef]
66. Wang Z,, Zhang J . 2011. Impact of gene expression noise on organismal fitness and the efficacy of natural selection. Proc Natl Acad Sci USA 108 : E67 E76. [CrossRef] [CrossRef]
67. Javid B,, Sorrentino F,, Toosky M,, Zheng W,, Pinkham JT,, Jain N,, Pan M,, Deighan P,, Rubin EJ . 2014. Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance. Proc Natl Acad Sci USA 111 : 1132 1137. [CrossRef] [CrossRef]
68. Avraham R,, Haseley N,, Brown D,, Penaranda C,, Jijon HB,, Trombetta JJ,, Satija R,, Shalek AK,, Xavier RJ,, Regev A,, Hung DT . 2015. Pathogen cell-to-cell variability drives heterogeneity in host immune responses. Cell 162 : 1309 1321. [CrossRef] [CrossRef]
69. Davis KM,, Mohammadi S,, Isberg RR . 2015. Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack. Cell Host Microbe 17 : 21 31. [CrossRef] [CrossRef]
70. Guantes R,, Benedetti I,, Silva-Rocha R,, de Lorenzo V . 2016. Transcription factor levels enable metabolic diversification of single cells of environmental bacteria. ISME J 10 : 1122 1133. [CrossRef] [CrossRef]
71. Schreiber F,, Littmann S,, Lavik G,, Escrig S,, Meibom A,, Kuypers MM,, Ackermann M . 2016. Phenotypic heterogeneity driven by nutrient limitation promotes growth in fluctuating environments. Nat Microbiol 1 : 16055. [CrossRef]
72. Sturm A,, Dworkin J . 2015. Phenotypic diversity as a mechanism to exit cellular dormancy. Curr Biol 25 : 2272 2277. [CrossRef] [CrossRef]
73. Mitchell A,, Romano GH,, Groisman B,, Yona A,, Dekel E,, Kupiec M,, Dahan O,, Pilpel Y . 2009. Adaptive prediction of environmental changes by microorganisms. Nature 460 : 220 224. [CrossRef] [CrossRef]
74. Shi L,, Jung Y-J,, Tyagi S,, Gennaro ML,, North RJ . 2003. Expression of Th1-mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence. Proc Natl Acad Sci USA 100 : 241 246. [CrossRef] [CrossRef]
75. Talaat AM,, Lyons R,, Howard ST,, Johnston SA . 2004. The temporal expression profile of Mycobacterium tuberculosis infection in mice. Proc Natl Acad Sci USA 101 : 4602 4607. [CrossRef] [CrossRef]
76. Rachman H,, Strong M,, Ulrichs T,, Grode L,, Schuchhardt J,, Mollenkopf H,, Kosmiadi GA,, Eisenberg D,, Kaufmann SHE . 2006. Unique transcriptome signature of Mycobacterium tuberculosis in pulmonary tuberculosis. Infect Immun 74 : 1233 1242. [CrossRef]
77. Rogerson BJ,, Jung YJ,, LaCourse R,, Ryan L,, Enright N,, North RJ . 2006. Expression levels of Mycobacterium tuberculosis antigen-encoding genes versus production levels of antigen-specific T cells during stationary level lung infection in mice. Immunology 118 : 195 201. [CrossRef] [CrossRef]
78. Rohde KH,, Abramovitch RB,, Russell DG . 2007. Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. Cell Host Microbe 2 : 352 364. [CrossRef] [CrossRef]
79. Flentie K,, Garner AL,, Stallings CL . 2016. Mycobacterium tuberculosis transcription machinery: ready to respond to host attacks. J Bacteriol 198 : 1360 1373. [CrossRef] [CrossRef]
80. Shi L,, Sohaskey CD,, Kana BD,, Dawes S,, North RJ,, Mizrahi V,, Gennaro ML . 2005. Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. Proc Natl Acad Sci USA 102 : 15629 15634. [CrossRef] [CrossRef]
81. Shi L,, Sohaskey CD,, Pfeiffer C,, Datta P,, Parks M,, McFadden J,, North RJ,, Gennaro ML . 2010. Carbon flux rerouting during Mycobacterium tuberculosis growth arrest. Mol Microbiol 78 : 1199 1215. [CrossRef] [CrossRef]
82. Balázsi G,, Heath AP,, Shi L,, Gennaro ML . 2008. The temporal response of the Mycobacterium tuberculosis gene regulatory network during growth arrest. Mol Syst Biol 4 : 225.[CrossRef] [CrossRef]
83. Baek S-H,, Li AH,, Sassetti CM . 2011. Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol 9 : e1001065. [CrossRef] [CrossRef]
84. Sukumar N,, Tan S,, Aldridge BB,, Russell DG . 2014. Exploitation of Mycobacterium tuberculosis reporter strains to probe the impact of vaccination at sites of infection. PLoS Pathog 10 : e1004394. [CrossRef] [CrossRef]
85. Bhaskar A,, Chawla M,, Mehta M,, Parikh P,, Chandra P,, Bhave D,, Kumar D,, Carroll KS,, Singh A . 2014. Reengineering redox sensitive GFP to measure mycothiol redox potential of Mycobacterium tuberculosis during infection. PLoS Pathog 10 : e1003902. [CrossRef] [CrossRef]
86. Baker JJ,, Johnson BK,, Abramovitch RB . 2014. Slow growth of Mycobacterium tuberculosis at acidic pH is regulated by phoPR and host-associated carbon sources. Mol Microbiol 94 : 56 69. [CrossRef] [CrossRef]
87. Liu Y,, Tan S,, Huang L,, Abramovitch RB,, Rohde KH,, Zimmerman MD,, Chen C,, Dartois V,, VanderVen BC,, Russell DG . 2016. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo . J Exp Med 213 : 809 825.[CrossRef] [CrossRef]
88. Arnoldini M,, Vizcarra IA,, Peña-Miller R,, Stocker N,, Diard M,, Vogel V,, Beardmore RE,, Hardt WD,, Ackermann M . 2014. Bistable expression of virulence genes in salmonella leads to the formation of an antibiotic-tolerant subpopulation. PLoS Biol 12 : e1001928.[CrossRef] [CrossRef]
89. Diard M,, Garcia V,, Maier L,, Remus-Emsermann MN,, Regoes RR,, Ackermann M,, Hardt WD . 2013. Stabilization of cooperative virulence by the expression of an avirulent phenotype. Nature 494 : 353 356. [CrossRef] [CrossRef]
90. Santi I,, Dhar N,, Bousbaine D,, Wakamoto Y,, McKinney JD . 2013. Single-cell dynamics of the chromosome replication and cell division cycles in mycobacteria. Nat Commun 4 : 2470.
91. Santi I,, McKinney JD . 2015. Chromosome organization and replisome dynamics in Mycobacterium smegmatis. MBio 6 : e01999-14.[CrossRef] [CrossRef]
92. Klumpp S,, Zhang Z,, Hwa T . 2009. Growth rate-dependent global effects on gene expression in bacteria. Cell 139 : 1366 1375. [CrossRef] [CrossRef]
93. Ray JCJ,, Tabor JJ,, Igoshin OA . 2011. Non-transcriptional regulatory processes shape transcriptional network dynamics. Nat Rev Microbiol 9 : 817 828. [CrossRef] [CrossRef]
94. Cerulus B,, New AM,, Pougach K,, Verstrepen KJ . 2016. Noise and epigenetic inheritance of single-cell division times influence population fitness. Curr Biol 26 : 1138 1147. [CrossRef] [CrossRef]
95. Hashimoto M,, Nozoe T,, Nakaoka H,, Okura R,, Akiyoshi S,, Kaneko K,, Kussell E,, Wakamoto Y . 2016. Noise-driven growth rate gain in clonal cellular populations. Proc Natl Acad Sci USA 113 : 3251 3256. [CrossRef] [CrossRef]
96. Muñoz-Elías EJ,, Timm J,, Botha T,, Chan WT,, Gomez JE,, McKinney JD . 2005. Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infect Immun 73 : 546 551. [CrossRef] [CrossRef]
97. Gill WP,, Harik NS,, Whiddon MR,, Liao RP,, Mittler JE,, Sherman DR . 2009. A replication clock for Mycobacterium tuberculosis . Nat Med 15 : 211 214. [CrossRef] [CrossRef]
98. Raffetseder J,, Pienaar E,, Blomgran R,, Eklund D,, Patcha Brodin V,, Andersson H,, Welin A,, Lerm M . 2014. Replication rates of Mycobacterium tuberculosis in human macrophages do not correlate with mycobacterial antibiotic susceptibility. PLoS One 9 : e112426. [CrossRef] [CrossRef]
99. Ufimtseva E . 2015. Mycobacterium-host cell relationships in granulomatous lesions in a mouse model of latent tuberculous infection. BioMed Res Int 2015 : 948131. [CrossRef] [CrossRef]
100. Vandiviere HM,, Loring WE,, Melvin I,, Willis S . 1956. The treated pulmonary lesion and its tubercle bacillus. II. The death and resurrection. Am J Med Sci 232 : 30 37; passim[CrossRef] [CrossRef]
101. Dhillon J,, Fourie PB,, Mitchison DA . 2014. Persister populations of Mycobacterium tuberculosis in sputum that grow in liquid but not on solid culture media. J Antimicrob Chemother 69 : 437 440. [CrossRef] [CrossRef]
102. Mukamolova GV,, Turapov O,, Malkin J,, Woltmann G,, Barer MR . 2010. Resuscitation-promoting factors reveal an occult population of tubercle Bacilli in Sputum. Am J Respir Crit Care Med 181 : 174 180. [CrossRef] [CrossRef]
103. Nikitushkin VD,, Demina GR,, Shleeva MO,, Kaprelyants AS . 2013. Peptidoglycan fragments stimulate resuscitation of “non-culturable” mycobacteria. Antonie van Leeuwenhoek 103 : 37 46. [CrossRef] [CrossRef]
104. Garton NJ,, Waddell SJ,, Sherratt AL,, Lee SM,, Smith RJ,, Senner C,, Hinds J,, Rajakumar K,, Adegbola RA,, Besra GS,, Butcher PD,, Barer MR . 2008. Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med 5 : 0364 0645.[CrossRef]
105. Dhar N,, Manina G . 2015. Single-cell analysis of mycobacteria using microfluidics and time-lapse microscopy. Methods Mol Biol 1285 : 241 256. [CrossRef] [CrossRef]
106. Manina G,, McKinney JD . 2013. A single-cell perspective on non-growing but metabolically active (NGMA) bacteria. Curr Top Microbiol Immunol 374 : 135 161. [CrossRef] [CrossRef]
107. Mouton JM,, Helaine S,, Holden DW,, Sampson SL . 2016. Elucidating population-wide mycobacterial replication dynamics at the single-cell level. Microbiology 162 : 966 978. [CrossRef] [CrossRef]
108. Helaine S,, Cheverton AM,, Watson KG,, Faure LM,, Matthews SA,, Holden DW . 2014. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343 : 204 208. [CrossRef] [CrossRef]
109. Adams KN,, Takaki K,, Connolly LE,, Wiedenhoft H,, Winglee K,, Humbert O,, Edelstein PH,, Cosma CL,, Ramakrishnan L . 2011. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145 : 39 53. [CrossRef] [CrossRef]
110. Nyström T . 2007. A bacterial kind of aging. PLoS Genet 3 : e224. [CrossRef] [CrossRef]
111. Stewart EJ,, Madden R,, Paul G,, Taddei F . 2005. Aging and death in an organism that reproduces by morphologically symmetric division. PLoS Biol 3 : e45. [CrossRef] [CrossRef]
112. Wang P,, Robert L,, Pelletier J,, Dang WL,, Taddei F,, Wright A,, Jun S . 2010. Robust growth of Escherichia coli . Curr Biol 20 : 1099 1103. [CrossRef] [CrossRef]
113. Lindner AB,, Madden R,, Demarez A,, Stewart EJ,, Taddei F . 2008. Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation. Proc Natl Acad Sci USA 105 : 3076 3081. [CrossRef] [CrossRef]
114. Clark MW,, Yie AM,, Eder EK,, Dennis RG,, Basting PJ,, Martinez KA II,, Jones BD,, Slonczewski JL . 2015. Periplasmic acid stress increases cell division asymmetry (polar aging) of Escherichia coli . PLoS One 10 : e0144650. [CrossRef] [CrossRef]
115. Aldridge BB,, Fernandez-Suarez M,, Heller D,, Ambravaneswaran V,, Irimia D,, Toner M,, Fortune SM . 2012. Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility. Science 335 : 100 104. [CrossRef] [CrossRef]
116. Joyce G,, Williams KJ,, Robb M,, Noens E,, Tizzano B,, Shahrezaei V,, Robertson BD . 2012. Cell division site placement and asymmetric growth in mycobacteria. PLoS One 7 : e44582.[CrossRef] [CrossRef]
117. Singh B,, Nitharwal RG,, Ramesh M,, Pettersson BMF,, Kirsebom LA,, Dasgupta S . 2013. Asymmetric growth and division in Mycobacterium spp.: compensatory mechanisms for non-medial septa. Mol Microbiol 88 : 64 76. [CrossRef] [CrossRef]
118. Kieser KJ,, Rubin EJ . 2014. How sisters grow apart: mycobacterial growth and division. Nat Rev Microbiol 12 : 550 562. [CrossRef] [CrossRef]
119. Aguilaniu H,, Gustafsson L,, Rigoulet M,, Nyström T . 2003. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science 299 : 1751 1753. [CrossRef] [CrossRef]
120. Winkler J,, Seybert A,, König L,, Pruggnaller S,, Haselmann U,, Sourjik V,, Weiss M,, Frangakis AS,, Mogk A,, Bukau B . 2010. Quantitative and spatio-temporal features of protein aggregation in Escherichia coli and consequences on protein quality control and cellular ageing. EMBO J 29 : 910 923. [CrossRef] [CrossRef]
121. Bufalino MR,, DeVeale B,, van der Kooy D . 2013. The asymmetric segregation of damaged proteins is stem cell-type dependent. J Cell Biol 201 : 523 530. [CrossRef] [CrossRef]
122. Vaubourgeix J,, Lin G,, Dhar N,, Chenouard N,, Jiang X,, Botella H,, Lupoli T,, Mariani O,, Yang G,, Ouerfelli O,, Unser M,, Schnappinger D,, McKinney J,, Nathan C . 2015. Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells. Cell Host Microbe 17 : 178 190. [CrossRef] [CrossRef]
123. Fay A,, Glickman MS . 2014. An essential nonredundant role for mycobacterial DnaK in native protein folding. PLoS Genet 10 : e1004516. [CrossRef] [CrossRef]
124. Feng J,, Kessler DA,, Ben-Jacob E,, Levine H . 2014. Growth feedback as a basis for persister bistability. Proc Natl Acad Sci USA 111 : 544 549. [CrossRef] [CrossRef]
125. Fasani RA,, Savageau MA . 2013. Molecular mechanisms of multiple toxin-antitoxin systems are coordinated to govern the persister phenotype. Proc Natl Acad Sci USA 110 : E2528 E2537. [CrossRef] [CrossRef]
126. Rotem E,, Loinger A,, Ronin I,, Levin-Reisman I,, Gabay C,, Shoresh N,, Biham O,, Balaban NQ . 2010. Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence. Proc Natl Acad Sci USA 107 : 12541 12546. [CrossRef] [CrossRef]
127. Maisonneuve E,, Castro-Camargo M,, Gerdes K . 2013. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 154 : 1140 1150. [CrossRef] [CrossRef]
128. Germain E,, Roghanian M,, Gerdes K,, Maisonneuve E . 2015. Stochastic induction of persister cells by HipA through (p)ppGpp-mediated activation of mRNA endonucleases. Proc Natl Acad Sci USA 112 : 5171 5176. [CrossRef] [CrossRef]
129. Ramage HR,, Connolly LE,, Cox JS . 2009. Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet 5 : e1000767.[CrossRef] [CrossRef]
130. Sala A,, Bordes P,, Genevaux P . 2014. Multiple toxin-antitoxin systems in Mycobacterium tuberculosis . Toxins (Basel) 6 : 1002 1020. [CrossRef] [CrossRef]
131. Keren I,, Minami S,, Rubin E,, Lewis K . 2011. Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio 2 : e00100-11. [CrossRef] [CrossRef]
132. Cortes T,, Schubert OT,, Rose G,, Arnvig KB,, Comas I,, Aebersold R,, Young DB . 2013. Genome-wide mapping of transcriptional start sites defines an extensive leaderless transcriptome in Mycobacterium tuberculosis . Cell Reports 5 : 1121 1131 (Erratum 6:415). [CrossRef]
133. Albrethsen J,, Agner J,, Piersma SR,, Højrup P,, Pham TV,, Weldingh K,, Jimenez CR,, Andersen P,, Rosenkrands I . 2013. Proteomic profiling of Mycobacterium tuberculosis identifies nutrient-starvation-responsive toxin-antitoxin systems. Mol Cell Proteomics 12 : 1180 1191. [CrossRef] [CrossRef]
134. Fivian-Hughes AS,, Davis EO . 2010. Analyzing the regulatory role of the HigA antitoxin within Mycobacterium tuberculosis . J Bacteriol 192 : 4348 4356. [CrossRef] [CrossRef]
135. Bordes P,, Cirinesi AM,, Ummels R,, Sala A,, Sakr S,, Bitter W,, Genevaux P . 2011. SecB-like chaperone controls a toxin-antitoxin stress-responsive system in Mycobacterium tuberculosis . Proc Natl Acad Sci USA 108 : 8438 8443. [CrossRef] [CrossRef]
136. Schuessler DL,, Cortes T,, Fivian-Hughes AS,, Lougheed KEA,, Harvey E,, Buxton RS,, Davis EO,, Young DB . 2013. Induced ectopic expression of HigB toxin in Mycobacterium tuberculosis results in growth inhibition, reduced abundance of a subset of mRNAs and cleavage of tmRNA. Mol Microbiol 90 : 195 207.
137. Torrey HL,, Keren I,, Via LE,, Lee JS,, Lewis K . 2016. High persister mutants in Mycobacterium tuberculosis . PLoS One 11 : e0155127. [CrossRef] [CrossRef]
138. Tiwari P,, Arora G,, Singh M,, Kidwai S,, Narayan OP,, Singh R . 2015. MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs. Nat Commun 6 : 6059. [CrossRef] [CrossRef]
139. Schifano JM,, Cruz JW,, Vvedenskaya IO,, Edifor R,, Ouyang M,, Husson RN,, Nickels BE,, Woychik NA . 2016. tRNA is a new target for cleavage by a MazF toxin. Nucleic Acids Res 44 : 1256 1270. [CrossRef] [CrossRef]
140. Korch SB,, Contreras H,, Clark-Curtiss JE . 2009. Three Mycobacterium tuberculosis Rel toxin-antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. J Bacteriol 191 : 1618 1630. [CrossRef] [CrossRef]
141. Korch SB,, Malhotra V,, Contreras H,, Clark-Curtiss JE . 2015. The Mycobacterium tuberculosis relBE toxin:antitoxin genes are stress-responsive modules that regulate growth through translation inhibition. J Microbiol 53 : 783 795. [CrossRef] [CrossRef]
142. Robson J,, McKenzie JL,, Cursons R,, Cook GM,, Arcus VL . 2009. The vapBC operon from Mycobacterium smegmatis is an autoregulated toxin-antitoxin module that controls growth via inhibition of translation. J Mol Biol 390 : 353 367. [CrossRef] [CrossRef]
143. Ahidjo BA,, Kuhnert D,, McKenzie JL,, Machowski EE,, Gordhan BG,, Arcus V,, Abrahams GL,, Mizrahi V . 2011. VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. PLoS One 6 : e21738. [CrossRef] [CrossRef]
144. Andrews ES,, Arcus VL . 2015. The mycobacterial PhoH2 proteins are type II toxin antitoxins coupled to RNA helicase domains. Tuberculosis (Edinb) 95 : 385 394. [CrossRef] [CrossRef]
145. Cruz JW,, Sharp JD,, Hoffer ED,, Maehigashi T,, Vvedenskaya IO,, Konkimalla A,, Husson RN,, Nickels BE,, Dunham CM,, Woychik NA . 2015. Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase. Nat Commun 6 : 7480. [CrossRef] [CrossRef]
146. McKenzie JL,, Robson J,, Berney M,, Smith TC,, Ruthe A,, Gardner PP,, Arcus VL,, Cook GM . 2012. A VapBC toxin-antitoxin module is a posttranscriptional regulator of metabolic flux in mycobacteria. J Bacteriol 194 : 2189 2204. [CrossRef] [CrossRef]
147. Walter ND,, Dolganov GM,, Garcia BJ,, Worodria W,, Andama A,, Musisi E,, Ayakaka I,, Van TT,, Voskuil MI,, de Jong BC,, Davidson RM,, Fingerlin TE,, Kechris K,, Palmer C,, Nahid P,, Daley CL,, Geraci M,, Huang L,, Cattamanchi A,, Strong M,, Schoolnik GK,, Davis JL . 2015. Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J Infect Dis 212 : 990 998. [CrossRef] [CrossRef]
148. Comstock GW . 1982. Epidemiology of tuberculosis. Am Rev Respir Dis 125 : 8 15.
149. Canetti G . 1968. Biology of the mycobacterioses. Pathogenesis of tuberculosis in man. Ann N Y Acad Sci 154( 1 Biology of My) : 13 18. [CrossRef] [CrossRef]
150. Dannenberg AM Jr . 2006. Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC.[CrossRef] [CrossRef]
151. Via LE,, Schimel D,, Weiner DM,, Dartois V,, Dayao E,, Cai Y,, Yoon Y-S,, Dreher MR,, Kastenmayer RJ,, Laymon CM,, Carny JE,, Flynn JL,, Herscovitch P,, Barry CE III . 2012. Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [ 18F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother 56 : 4391 4402. [CrossRef] [CrossRef]
152. Via LE,, Weiner DM,, Schimel D,, Lin PL,, Dayao E,, Tankersley SL,, Cai Y,, Coleman MT,, Tomko J,, Paripati P,, Orandle M,, Kastenmayer RJ,, Tartakovsky M,, Rosenthal A,, Portevin D,, Eum SY,, Lahouar S,, Gagneux S,, Young DB,, Flynn JL,, Barry CE III . 2013. Differential virulence and disease progression following Mycobacterium tuberculosis complex infection of the common marmoset ( Callithrix jacchus). Infect Immun 81 : 2909 2919. [CrossRef] [CrossRef]
153. Bagci U,, Foster B,, Miller-Jaster K,, Luna B,, Dey B,, Bishai WR,, Jonsson CB,, Jain S,, Mollura DJ . 2013. A computational pipeline for quantification of pulmonary infections in small animal models using serial PET-CT imaging. EJNMMI Res 3 : 55. [CrossRef] [CrossRef]
154. Murawski AM,, Gurbani S,, Harper JS,, Klunk M,, Younes L,, Jain SK,, Jedynak BM . 2014. Imaging the evolution of reactivation pulmonary tuberculosis in mice using 18F-FDG PET. J Nucl Med 55 : 1726 1729. [CrossRef] [CrossRef]
155. Dartois V . 2014. The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nat Rev Microbiol 12 : 159 167. [CrossRef] [CrossRef]
156. Ramakrishnan L . 2013. The zebrafish guide to tuberculosis immunity and treatment. Cold Spring Harb Symp Quant Biol 78 : 179 192. [CrossRef] [CrossRef]
157. Kramnik I,, Dietrich WF,, Demant P,, Bloom BR . 2000. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis . Proc Natl Acad Sci USA 97 : 8560 8565. [CrossRef] [CrossRef]
158. Manabe YC,, Kesavan AK,, Lopez-Molina J,, Hatem CL,, Brooks M,, Fujiwara R,, Hochstein K,, Pitt MLM,, Tufariello J,, Chan J,, McMurray DN,, Bishai WR,, Dannenberg AM Jr,, Mendez S . 2008. The aerosol rabbit model of TB latency, reactivation and immune reconstitution inflammatory syndrome. Tuberculosis (Edinb) 88 : 187 196. [CrossRef] [CrossRef]
159. Lin PL,, Rodgers M,, Smith L,, Bigbee M,, Myers A,, Bigbee C,, Chiosea I,, Capuano SV,, Fuhrman C,, Klein E,, Flynn JL . 2009. Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77 : 4631 4642. [CrossRef]
160. Pagán AJ,, Ramakrishnan L . 2014. Immunity and immunopathology in the tuberculous granuloma. Cold Spring Harb Perspect Med 5 : a018499. [CrossRef] [CrossRef]
161. Seimon TA,, Kim M-J,, Blumenthal A,, Koo J,, Ehrt S,, Wainwright H,, Bekker L-G,, Kaplan G,, Nathan C,, Tabas I,, Russell DG . 2010. Induction of ER stress in macrophages of tuberculosis granulomas. PLoS One 5 : e12772. [CrossRef] [CrossRef]
162. Sallusto F . 2016. Heterogeneity of Human CD4(+) T Cells Against Microbes. Annu Rev Immunol 34 : 317 334. [CrossRef] [CrossRef]
163. Nathan C . 2012. Fresh approaches to anti-infective therapies. Sci Trans Med 4 : 140sr2 140sr2.
164. Subbian S,, Tsenova L,, Kim M-J,, Wainwright HC,, Visser A,, Bandyopadhyay N,, Bader JS,, Karakousis PC,, Murrmann GB,, Bekker L-G,, Russell DG,, Kaplan G . 2015. Lesion-specific immune response in granulomas of patients with pulmonary tuberculosis: a pilot study. PLoS One 10 : e0132249 [CrossRef]. [CrossRef]
165. Kim M-J,, Wainwright HC,, Locketz M,, Bekker L-G,, Walther GB,, Dittrich C,, Visser A,, Wang W,, Hsu F-F,, Wiehart U,, Tsenova L,, Kaplan G,, Russell DG . 2010. Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism. EMBO Mol Med 2 : 258 274. [CrossRef] [CrossRef]
166. Peyron P,, Vaubourgeix J,, Poquet Y,, Levillain F,, Botanch C,, Bardou F,, Daffé M,, Emile J-F,, Marchou B,, Cardona P-J,, de Chastellier C,, Altare F . 2008. Foamy macrophages from tuberculous patients’ granulomas constitute a nutrient-rich reservoir for M. tuberculosis persistence. PLoS Pathog 4 : e1000204. [CrossRef] [CrossRef]
167. Mattila JT,, Ojo OO,, Kepka-Lenhart D,, Marino S,, Kim JH,, Eum SY,, Via LE,, Barry CE III,, Klein E,, Kirschner DE,, Morris SM Jr,, Lin PL,, Flynn JL . 2013. Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191 : 773 784. [CrossRef] [CrossRef]
168. Irwin SM,, Driver E,, Lyon E,, Schrupp C,, Ryan G,, Gonzalez-Juarrero M,, Basaraba RJ,, Nuermberger EL,, Lenaerts AJ . 2015. Presence of multiple lesion types with vastly different microenvironments in C3HeB/FeJ mice following aerosol infection with Mycobacterium tuberculosis . Dis Model Mech 8 : 591 602. [CrossRef] [CrossRef]
169. Martin CJ,, Carey AF,, Fortune SM . 2016. A bug’s life in the granuloma. Semin Immunopathol 38 : 213 220. [CrossRef] [CrossRef]
170. Lin PL,, Dartois V,, Johnston PJ,, Janssen C,, Via L,, Goodwin MB,, Klein E,, Barry CE III,, Flynn JL . 2012. Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc Natl Acad Sci USA 109 : 14188 14193. [CrossRef] [CrossRef]
171. Chen RY,, Dodd LE,, Lee M,, Paripati P,, Hammoud DA,, Mountz JM,, Jeon D,, Zia N,, Zahiri H,, Coleman MT,, Carroll MW,, Lee JD,, Jeong YJ,, Herscovitch P,, Lahouar S,, Tartakovsky M,, Rosenthal A,, Somaiyya S,, Lee S,, Goldfeder LC,, Cai Y,, Via LE,, Park S-K,, Cho S-N,, Barry CE III . 2014. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Trans Med 6 : 265ra166.[CrossRef] [CrossRef]
172. Via LE,, England K,, Weiner DM,, Schimel D,, Zimmerman MD,, Dayao E,, Chen RY,, Dodd LE,, Richardson M,, Robbins KK,, Cai Y,, Hammoud D,, Herscovitch P,, Dartois V,, Flynn JL,, Barry CE III . 2015. A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets. Antimicrob Agents Chemother 59 : 4181 4189. [CrossRef] [CrossRef]
173. Cambier CJ,, Falkow S,, Ramakrishnan L . 2014. Host evasion and exploitation schemes of Mycobacterium tuberculosis . Cell 159 : 1497 1509. [CrossRef] [CrossRef]
174. Al Shammari B,, Shiomi T,, Tezera L,, Bielecka MK,, Workman V,, Sathyamoorthy T,, Mauri F,, Jayasinghe SN,, Robertson BD,, D’Armiento J,, Friedland JS,, Elkington PT . 2015. The extracellular matrix regulates granuloma necrosis in Tuberculosis. J Infect Dis 212 : 463 473. [CrossRef] [CrossRef]
175. Tobin DM,, Roca FJ,, Oh SF,, McFarland R,, Vickery TW,, Ray JP,, Ko DC,, Zou Y,, Bang ND,, Chau TTH,, Vary JC,, Hawn TR,, Dunstan SJ,, Farrar JJ,, Thwaites GE,, King M-C,, Serhan CN,, Ramakrishnan L . 2012. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148 : 434 446. [CrossRef] [CrossRef]
176. Mayer-Barber KD,, Andrade BB,, Oland SD,, Amaral EP,, Barber DL,, Gonzales J,, Derrick SC,, Shi R,, Kumar NP,, Wei W,, Yuan X,, Zhang G,, Cai Y,, Babu S,, Catalfamo M,, Salazar AM,, Via LE,, Barry CE III,, Sher A . 2014. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 511 : 99 103. [CrossRef] [CrossRef]
177. Jennewein J,, Matuszak J,, Walter S,, Felmy B,, Gendera K,, Schatz V,, Nowottny M,, Liebsch G,, Hensel M,, Hardt W-D,, Gerlach RG,, Jantsch J . 2015. Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence. Cell Microbiol 17 : 1833 1847. [CrossRef] [CrossRef]
178. Oehlers SH,, Cronan MR,, Scott NR,, Thomas MI,, Okuda KS,, Walton EM,, Beerman RW,, Crosier PS,, Tobin DM . 2015. Interception of host angiogenic signalling limits mycobacterial growth. Nature 517 : 612 615. [CrossRef] [CrossRef]