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Tuberculosis Host-Pathogen Interactions pp 23–42Cite as

The Silent Plague: Regulation of Latent Tuberculosis Infections

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Abstract

Nearly one-third of the world’s population carries viable tubercle bacilli in their bodies but do not display disease. This represents the clinical definition of a latently infected patient who can reactivate and produce active disease at any time. Despite a great deal of investigation, it remains unclear exactly where or what state the bacteria responsible, Mycobacterium tuberculosis, are in during this latent phase of infection and how they enter and leave dormancy. Neither the exact signals nor the complete regulatory pathways involved are fully understood. This review is not meant to be a comprehensive overview of tuberculosis latency, but is meant to briefly raise some of the more critical and controversial issues in the literature related to latent infections, focusing primarily on bacterial gene expression and offering suggestions for directions of future research. We conclude that there are several signals involved in establishment of the persistent state during latent infections and reactivation from that state that remain to be elucidated. Interestingly, the clinical definition of latency is not likely to be due to bacteria in the same state in all patients. The complexity of these events offers opportunities to combat tuberculosis through manipulation of the bacterial persistent state and the interacting host immune response. Exploitation of bacterial persistence during latent infections as well as the signals that control these events may be critical to the ultimate goal of eradicating this ongoing plague of mankind.

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References

  1. Ippoliti C. WHO targets elimination of TB in over 30 countries. Cent Eur J Public Health. 2014;22(3):158–63. WHO/ERS joint news release, July 3, 2014.

    Google Scholar 

  2. WHO. Global tuberculosis report 2013. Geneva: World Health Organization; 2013.

    Google Scholar 

  3. WHO. Global tuberculosis report 2016. Geneva: World Health Organization; 2016.

    Google Scholar 

  4. Bloom BR, Murray CJL. Tuberculosis: commentary on a reemergent killer. Science. 1992;257:1055–64.

    Article  CAS  PubMed  Google Scholar 

  5. Gedde-Dahl T. Tuberculous infection in the light of tuberculin matriculation. Am J Hyg. 1952;56:139–214.

    CAS  PubMed  Google Scholar 

  6. Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen VO, Andersen AB. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J Infect Dis. 2002;185:401–4.

    Article  CAS  PubMed  Google Scholar 

  7. Parrish NM, Dick JD, Bishai WR. Mechanisms of latency in Mycobacterium tuberculosis. Trends Microbiol. 1998;6:107–12.

    Article  CAS  PubMed  Google Scholar 

  8. Vynnycky E, Fine PE. Lifetime risks, incubation period, and serial interval of tuberculosis. Am J Epidemiol. 2000;152:247–63.

    Article  CAS  PubMed  Google Scholar 

  9. Barry CE 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol. 2009;7:845–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Manina G, Dhar N, McKinney JD. Stress and host immunity amplify Mycobacterium tuberculosis phenotypic heterogeneity and induce nongrowing metabolically active forms. Cell Host Microbe. 2015;17:32–46.

    Article  CAS  PubMed  Google Scholar 

  11. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res. 2011;50:202–12.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gill WP, Harik NS, Whiddon MR, Liao RP, Mittler JE, Sherman DR. A replication clock for Mycobacterium tuberculosis. Nat Med. 2009;15:211–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Munoz-Elias EJ, Timm J, Botha T, Chan WT, Gomez JE, McKinney JD. Replication dynamics of Mycobacterium tuberculosis in chronically infected mice. Infect Immun. 2005;73:546–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tufariello JM, Chan J, Flynn JL. Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. Lancet Infect Dis. 2003;3:578–90.

    Article  CAS  PubMed  Google Scholar 

  15. Wayne LG, Hayes LG. An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect Immun. 1996;64:2062–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. McCune RM Jr, McDermott W, Tompsett R. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J Exp Med. 1956;104:763–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McCune RM Jr, Tompsett R. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J Exp Med. 1956;104:737–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Scanga CA, Mohan VP, Joseph H, Yu K, Chan J, Flynn JL. Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect Immun. 1999;67:4531–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cunningham AF, Spreadbury CL. Mycobacterial stationary phase induced by low oxygen tension: cell wall thickening and localization of the 16-kilodalton alpha-crystallin homolog. J Bacteriol. 1998;180:801–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gold B, Warrier T, Nathan C. A multi-stress model for high throughput screening against non-replicating Mycobacterium tuberculosis. Methods Mol Biol. 2015;1285:293–315.

    Article  CAS  PubMed  Google Scholar 

  21. Imboden P, Schoolnik GK. Construction and characterization of a partial Mycobacterium tuberculosis cDNA library of genes expressed at reduced oxygen tension. Gene. 1998;213:107–17.

    Article  CAS  PubMed  Google Scholar 

  22. McKinney JD, Zu Bentrup KH, Munoz-Elias EJ, Miczak A, Chen B, Chan W-T, Swenson D, Sacchettini JC, Jacobs WR Jr, Russell DG. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature. 2000;406:735–8.

    Article  CAS  PubMed  Google Scholar 

  23. Hernandez-Pando R, Jeyanathan M, Mengistu G, Aguilar D, Orozco H, Harboe M, Rook GA, Bjune G. Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet. 2000;356:2133–8.

    Article  CAS  PubMed  Google Scholar 

  24. Opie EL, Aronson JD. Tubercle bacilli in latent tuberculosis lesions and in lung tissue without tuberculous lesions. Arch Pathol Lab Med. 1927;4:1–21.

    Google Scholar 

  25. Scanga CA, Mohan VP, Yu K, Joseph H, Tanaka K, Chan J, Flynn JL. Depletion of CD4(+) T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon gamma and nitric oxide synthase 2. J Exp Med. 2000;192:347–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Forrellad MA, McNeil M, Santangelo Mde L, Blanco FC, Garcia E, Klepp LI, Huff J, Niederweis M, Jackson M, Bigi F. Role of the Mce1 transporter in the lipid homeostasis of Mycobacterium tuberculosis. Tuberculosis (Edinb). 2014;94:170–7.

    Article  CAS  Google Scholar 

  27. Khan S, Islam A, Hassan MI, Ahmad F. Purification and structural characterization of Mce4A from Mycobacterium tuberculosis. Int J Biol Macromol. 2016;93:235–41.

    Article  CAS  PubMed  Google Scholar 

  28. Pandey AK, Sassetti CM. Mycobacterial persistence requires the utilization of host cholesterol. Proc Natl Acad Sci U S A. 2008;105:4376–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Daniel J, Sirakova T, Kolattukudy P. An acyl-CoA synthetase in Mycobacterium tuberculosis involved in triacylglycerol accumulation during dormancy. PLoS One. 2014;9:e114877.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. McGillivray A, Golden NA, Kaushal D. The Mycobacterium tuberculosis Clp gene regulator is required for in vitro reactivation from hypoxia-induced dormancy. J Biol Chem. 2015;290:2351–67.

    Article  CAS  PubMed  Google Scholar 

  31. Banaiee N, Jacobs WR Jr, Ernst JD. Regulation of Mycobacterium tuberculosis whiB3 in the mouse lung and macrophages. Infect Immun. 2006;74:6449–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gonzalo Asensio J, Maia C, Ferrer NL, Barilone N, Laval F, Soto CY, Winter N, Daffe M, Gicquel B, Martin C, Jackson M. The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis. J Biol Chem. 2006;281:1313–6.

    Article  PubMed  CAS  Google Scholar 

  33. He H, Hovey R, Kane J, Singh V, Zahrt TC. Mprab is a stress-responsive two-component system that directly regulates expression of sigma factors SigB and SigE in Mycobacterium tuberculosis. J Bacteriol. 2006;188:2134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mukamolova GV, Turapov OA, Young DI, Kaprelyants AS, Kell DB, Young M. A family of autocrine growth factors in Mycobacterium tuberculosis. Mol Microbiol. 2002;46:623–35.

    Article  CAS  PubMed  Google Scholar 

  35. Primm TP, Andersen SJ, Mizrahi V, Avarbock D, Rubin H, Barry CE 3rd. The stringent response of Mycobacterium tuberculosis is required for long-term survival. J Bacteriol. 2000;182:4889–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sherman DR, Voskuil M, Schnappinger D, Liao R, Harrell MI, Schoolnik GK. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin. Proc Natl Acad Sci U S A. 2001;98:7534–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Voskuil MI, Schnappinger D, Visconti KC, Harrell MI, Dolganov GM, Sherman DR, Schoolnik GK. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med. 2003;198:705–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zahrt TC, Deretic V. Mycobacterium tuberculosis signal transduction system required for persistent infections. Proc Natl Acad Sci U S A. 2001;98:12706–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sureka K, Ghosh B, Dasgupta A, Basu J, Kundu M, Bose I. Positive feedback and noise activate the stringent response regulator rel in mycobacteria. PLoS One. 2008;3:e1771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Micklinghoff JC, Breitinger KJ, Schmidt M, Geffers R, Eikmanns BJ, Bange FC. Role of the transcriptional regulator RamB (Rv0465c) in the control of the glyoxylate cycle in Mycobacterium tuberculosis. J Bacteriol. 2009;191:7260–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee JH, Geiman DE, Bishai WR. Role of stress response sigma factor SigG in Mycobacterium tuberculosis. J Bacteriol. 2008;190:1128–33.

    Article  CAS  PubMed  Google Scholar 

  42. Manganelli R, Voskuil MI, Schoolnik GK, Smith I. The Mycobacterium tuberculosis ECF sigma factor sigmaE: role in global gene expression and survival in macrophages. Mol Microbiol. 2001;41:423–37.

    Article  CAS  PubMed  Google Scholar 

  43. Gonzalo-Asensio J, Mostowy S, Harders-Westerveen J, Huygen K, Hernandez-Pando R, Thole J, Behr M, Gicquel B, Martin C. PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PLoS One. 2008;3:e3496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Sinha A, Gupta S, Bhutani S, Pathak A, Sarkar D. PhoP-PhoP interaction at adjacent PhoP binding sites is influenced by protein phosphorylation. J Bacteriol. 2008;190:1317–28.

    Article  CAS  PubMed  Google Scholar 

  45. Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I. The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol Microbiol. 2006;60:312–30.

    Article  CAS  PubMed  Google Scholar 

  46. Guo M, Feng H, Zhang J, Wang W, Wang Y, Li Y, Gao C, Chen H, Feng Y, He ZG. Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system. Genome Res. 2009;19:1301–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boon C, Dick T. How Mycobacterium tuberculosis goes to sleep: the dormancy survival regulator DosR a decade later. Future Microbiol. 2012;7:513–8.

    Article  CAS  PubMed  Google Scholar 

  48. Lenaerts AJ, Hoff D, Aly S, Ehlers S, Andries K, Cantarero L, Orme IM, Basaraba RJ. Location of persisting mycobacteria in the Guinea pig model of tuberculosis revealed by R207910. Antimicrob Agents Chemother. 2007;51:3338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rustad TR, Sherrid AM, Minch KJ, Sherman DR. Hypoxia: a window into Mycobacterium tuberculosis latency. Cell Microbiol. 2009;11:1151–9.

    Article  CAS  PubMed  Google Scholar 

  50. Schreuder LJ, Parish T. Mycobacterium tuberculosis DosR is required for activity of the PmbtB and PmbtI promoters under hypoxia. PLoS One. 2014;9:e107283.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Via LE, Lin PL, Ray SM, Carrillo J, Allen SS, Eum SY, Taylor K, Klein E, Manjunatha U, Gonzales J, Lee EG, Park SK, Raleigh JA, Cho SN, McMurray DN, Flynn JL, Barry CE 3rd. Tuberculous granulomas are hypoxic in Guinea pigs, rabbits, and nonhuman primates. Infect Immun. 2008;76:2333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rodriguez JG, Hernandez AC, Helguera-Repetto C, Aguilar Ayala D, Guadarrama-Medina R, Anzola JM, Bustos JR, Zambrano MM, Gonzalez YMJ, Garcia MJ, Del Portillo P. Global adaptation to a lipid environment triggers the dormancy-related phenotype of Mycobacterium tuberculosis. MBio. 2014;5:e01125–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Ranganathan S, Bai G, Lyubetskaya A, Knapp GS, Peterson MW, Gazdik M, Al CG, Galagan JE, McDonough KA. Characterization of a camp responsive transcription factor, Cmr (Rv1675c), in TB complex mycobacteria reveals overlap with the DosR (DevR) dormancy regulon. Nucleic Acids Res. 2016;44:134–51.

    Article  CAS  PubMed  Google Scholar 

  54. Avarbock A, Avarbock D, Teh JS, Buckstein M, Wang ZM, Rubin H. Functional regulation of the opposing (p)ppGpp synthetase/hydrolase activities of RelMtb from Mycobacterium tuberculosis. Biochemistry. 2005;44:9913–23.

    Article  CAS  PubMed  Google Scholar 

  55. Boutte CC, Crosson S. Bacterial lifestyle shapes stringent response activation. Trends Microbiol. 2013;21:174–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dahl JL, Kraus CN, Boshoff HI, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry CE 3rd. The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proc Natl Acad Sci U S A. 2003;100:10026–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rifat D, Bishai WR, Karakousis PC. Phosphate depletion: a novel trigger for Mycobacterium tuberculosis persistence. J Infect Dis. 2009;200:1126–35.

    Article  CAS  PubMed  Google Scholar 

  58. Weiss LA, Stallings CL. Essential roles for Mycobacterium tuberculosis Rel beyond the production of (p)ppGpp. J Bacteriol. 2013;195:5629–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, Campos-Neto A. CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013;5:170ra13.

    PubMed  PubMed Central  Google Scholar 

  60. Garhyan J, Bhuyan S, Pulu I, Kalita D, Das B, Bhatnagar R. Preclinical and clinical evidence of Mycobacterium tuberculosis persistence in the hypoxic niche of bone marrow mesenchymal stem cells after therapy. Am J Pathol. 2015;185:1924–34.

    Article  PubMed  Google Scholar 

  61. Tornack J, Reece ST, Bauer WM, Vogelzang A, Bandermann S, Zedler U, Stingl G, Kaufmann SH, Melchers F. Human and mouse hematopoietic stem cells are a depot for dormant mycobacterium tuberculosis. PLoS One. 2017;12:e0169119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Deb C, Lee CM, Dubey VS, Daniel J, Abomoelak B, Sirakova TD, Pawar S, Rogers L, Kolattukudy PE. A novel in vitro multiple-stress dormancy model for Mycobacterium tuberculosis generates a lipid-loaded, drug-tolerant, dormant pathogen. PLoS One. 2009;4:e6077.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Carroll MW, Jeon D, Mountz JM, Lee JD, Jeong YJ, Zia N, Lee M, Lee J, Via LE, Lee S, Eum SY, Lee SJ, Goldfeder LC, Cai Y, Jin B, Kim Y, Oh T, Chen RY, Dodd LE, Gu W, Dartois V, Park SK, Kim CT, Barry CE 3rd, Cho SN. Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2013;57:3903–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Desai CR, Heera S, Patel A, Babrekar AB, Mahashur AA, Kamat SR. Role of metronidazole in improving response and specific drug sensitivity in advanced pulmonary tuberculosis. J Assoc Physicians India. 1989;37:694–7.

    CAS  PubMed  Google Scholar 

  65. Lin PL, Flynn JL. Understanding latent tuberculosis: a moving target. J Immunol. 2010;185:15–22.

    Article  CAS  PubMed  Google Scholar 

  66. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, Ioerger T, Sacchettini J, Fortune SM, Flynn JL. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2014;20:75–9.

    Article  CAS  PubMed  Google Scholar 

  67. Lin PL, Maiello P, Gideon HP, Coleman MT, Cadena AM, Rodgers MA, Gregg R, O’malley M, Tomko J, Fillmore D, Frye LJ, Rutledge T, Difazio RM, Janssen C, Klein E, Andersen PL, Fortune SM, Flynn JL. Pet CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog. 2016;12:e1005739.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Lin PL, Pawar S, Myers A, Pegu A, Fuhrman C, Reinhart TA, Capuano SV, Klein E, Flynn JL. Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun. 2006;74:3790–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lin PL, Rodgers M, Smith L, Bigbee M, Myers A, Bigbee C, Chiosea I, Capuano SV, Fuhrman C, Klein E, Flynn JL. Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun. 2009;77:4631–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jacobs WR Jr, Kalpana GV, Cirillo JD, Pascopella L, Udani RA, Jones WD Jr, Barletta RG, Bloom BR. Genetic systems for the mycobacteria. Methods Enzymol. 1991;204:537–55.

    Article  CAS  PubMed  Google Scholar 

  71. Jacobs WR Jr, Tuckman M, Bloom BR. Introduction of foreign DNA into mycobacteria using a shuttle phasmid. Nature. 1987;327:532–6.

    Article  CAS  PubMed  Google Scholar 

  72. Gautam US, McGillivray A, Mehra S, Didier PJ, Midkiff CC, Kissee RS, Golden NA, Alvarez X, Niu T, Rengarajan J, Sherman DR, Kaushal D. DosS is required for the complete virulence of Mycobacterium tuberculosis in mice with classical granulomatous lesions. Am J Respir Cell Mol Biol. 2015;52:708–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stallings CL, Stephanou NC, Chu L, Hochschild A, Nickels BE, Glickman MS. CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell. 2009;138:146–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ryndak MB, Singh KK, Peng Z, Laal S. Transcriptional profile of Mycobacterium tuberculosis replicating in type II alveolar epithelial cells. PLoS One. 2015;10:e0123745.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Fang H, Yu D, Hong Y, Zhou X, Li C, Sun B. The LuxR family regulator Rv0195 modulates Mycobacterium tuberculosis dormancy and virulence. Tuberculosis (Edinb). 2013;93:425–31.

    Article  CAS  Google Scholar 

  76. Converse PJ, Karakousis PC, Klinkenberg LG, Kesavan AK, Ly LH, Allen SS, Grosset JH, Jain SK, Lamichhane G, Manabe YC, McMurray DN, Nuermberger EL, Bishai WR. The role of the dosR/dosS two-component regulatory system in Mycobacterium tuberculosis virulence in three animal models. Infect Immun. 2009;77:1230–7.

    Article  CAS  PubMed  Google Scholar 

  77. Cirillo SL, Subbian S, Chen B, Weisbrod TR, Jacobs WR Jr, Cirillo JD. Protection of Mycobacterium tuberculosis from reactive oxygen species conferred by the mel2 locus impacts persistence and dissemination. Infect Immun. 2009;77:2557–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Modlin RL, Bloom BR. TB or not TB: that is no longer the question. Sci Transl Med. 2013;5:213sr6.

    Article  PubMed  Google Scholar 

  79. Turapov O, O’connor BD, Sarybaeva AA, Williams C, Patel H, Kadyrov AS, Sarybaev AS, Woltmann G, Barer MR, Mukamolova GV. Phenotypically adapted Mycobacterium tuberculosis populations from sputum are tolerant to first-line drugs. Antimicrob Agents Chemother. 2016;60:2476–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Garton NJ, Waddell SJ, Sherratt AL, Lee SM, Smith RJ, Senner C, Hinds J, Rajakumar K, Adegbola RA, Besra GS, Butcher PD, Barer MR. Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum. PLoS Med. 2008;5:e75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Mukamolova GV, Murzin AG, Salina EG, Demina GR, Kell DB, Kaprelyants AS, Young M. Muralytic activity of Micrococcus luteus Rpf and its relationship to physiological activity in promoting bacterial growth and resuscitation. Mol Microbiol. 2006;59:84–98.

    Article  CAS  PubMed  Google Scholar 

  82. Telkov MV, Demina GR, Voloshin SA, Salina EG, Dudik TV, Stekhanova TN, Mukamolova GV, Kazaryan KA, Goncharenko AV, Young M, Kaprelyants AS. Proteins of the Rpf (resuscitation promoting factor) family are peptidoglycan hydrolases. Biochemistry (Mosc). 2006;71:414–22.

    Article  CAS  Google Scholar 

  83. Downing KJ, Mischenko VV, Shleeva MO, Young DI, Young M, Kaprelyants AS, Apt AS, Mizrahi V. Mutants of Mycobacterium tuberculosis lacking three of the five rpf-like genes are defective for growth in vivo and for resuscitation in vitro. Infect Immun. 2005;73:3038–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kaprelyants AS, Gottschal JC, Kell DB. Dormancy in non-sporulating bacteria. FEMS Microbiol Rev. 1993;10:271–85.

    Article  CAS  PubMed  Google Scholar 

  85. Mukamolova GV, Kaprelyants AS, Kell DB, Young M. Adoption of the transiently non-culturable state--a bacterial survival strategy? Adv Microb Physiol. 2003;47:65–129.

    Article  CAS  PubMed  Google Scholar 

  86. Mukamolova GV, Kaprelyants AS, Young DI, Young M, Kell DB. A bacterial cytokine. Proc Natl Acad Sci U S A. 1998;95:8916–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mukamolova GV, Turapov OA, Kazarian K, Telkov M, Kaprelyants AS, Kell DB, Young M. The rpf gene of Micrococcus luteus encodes an essential secreted growth factor. Mol Microbiol. 2002;46:611–21.

    Article  CAS  PubMed  Google Scholar 

  88. Mukamolova GV, Yanopolskaya ND, Kell DB, Kaprelyants AS. On resuscitation from the dormant state of Micrococcus luteus. Antonie Van Leeuwenhoek. 1998;73:237–43.

    Article  CAS  PubMed  Google Scholar 

  89. Cohen-Gonsaud M, Barthe P, Bagneris C, Henderson B, Ward J, Roumestand C, Keep NH. The structure of a resuscitation-promoting factor domain from Mycobacterium tuberculosis shows homology to lysozymes. Nat Struct Mol Biol. 2005;12:270–3.

    Article  CAS  PubMed  Google Scholar 

  90. Cohen-Gonsaud M, Keep NH, Davies AP, Ward J, Henderson B, Labesse G. Resuscitation-promoting factors possess a lysozyme-like domain. Trends Biochem Sci. 2004;29:7–10.

    Article  CAS  PubMed  Google Scholar 

  91. Dziarski R, Gupta D. Review: mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity. Innate Immun. 2010;16:168–74.

    Article  CAS  PubMed  Google Scholar 

  92. Gelius E, Persson C, Karlsson J, Steiner H. A mammalian peptidoglycan recognition protein with N-acetylmuramoyl-L-alanine amidase activity. Biochem Biophys Res Commun. 2003;306:988–94.

    Article  CAS  PubMed  Google Scholar 

  93. Long R, Gardam M. Tumour necrosis factor-alpha inhibitors and the reactivation of latent tuberculosis infection. CMAJ. 2003;168:1153–6.

    PubMed  PubMed Central  Google Scholar 

  94. Manabe YC, Kesavan AK, Lopez-Molina J, Hatem CL, Brooks M, Fujiwara R, Hochstein K, Pitt ML, Tufariello J, Chan J, McMurray DN, Bishai WR, Dannenberg AM Jr, Mendez S. The aerosol rabbit model of TB latency, reactivation and immune reconstitution inflammatory syndrome. Tuberculosis (Edinb). 2008;88:187–96.

    Article  CAS  Google Scholar 

  95. Miller EA, Ernst JD. Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed. J Clin Invest. 2009;119:1079–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tufariello JM, Mi K, Xu J, Manabe YC, Kesavan AK, Drumm J, Tanaka K, Jacobs WR Jr, Chan J. Deletion of the Mycobacterium tuberculosis resuscitation-promoting factor Rv1009 gene results in delayed reactivation from chronic tuberculosis. Infect Immun. 2006;74:2985–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cheng Y, Xie H, Sule P, Hassounah H, Graviss EA, Kong Y, Cirillo JD, Rao J. Fluorogenic probes with substitutions at the 2 and 7 positions of cephalosporin are highly BlaC-specific for rapid Mycobacterium tuberculosis detection. Angew Chem Int Ed Engl. 2014;53:9360–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kong Y, Yao H, REN H, Subbian S, Cirillo SL, Sacchettini JC, Rao J, Cirillo JD. Imaging tuberculosis with endogenous beta-lactamase reporter enzyme fluorescence in live mice. Proc Natl Acad Sci U S A. 2010;107:12239–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Xie H, Mire J, Kong Y, Chang M, Hassounah HA, Thornton CN, Sacchettini JC, Cirillo JD, Rao J. Rapid point-of-care detection of the tuberculosis pathogen using a BlaC-specific fluorogenic probe. Nat Chem. 2012;4:802–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang HJ, Kong Y, Cheng Y, Janagama H, Hassounah H, Xie H, Rao J, Cirillo JD. Real-time imaging of Mycobacterium tuberculosis, using a novel near-infrared fluorescent substrate. J Infect Dis. 2017;215:405–14.

    CAS  PubMed  Google Scholar 

  101. Serra-Vidal MM, Latorre I, Franken KL, Diaz J, De Souza-Galvao ML, Casas I, Maldonado J, Mila C, Solsona J, Jimenez-Fuentes MA, Altet N, Lacoma A, Ruiz-Manzano J, Ausina V, Prat C, Ottenhoff TH, Dominguez J. Immunogenicity of 60 novel latency-related antigens of Mycobacterium tuberculosis. Front Microbiol. 2014;5:517.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Black GF, Thiel BA, Ota MO, Parida SK, Adegbola R, Boom WH, Dockrell HM, Franken KL, Friggen AH, Hill PC, Klein MR, Lalor MK, Mayanja H, Schoolnik G, Stanley K, Weldingh K, Kaufmann SH, Walzl G, Ottenhoff TH, GCGH Biomarkers for TB Consortium. Immunogenicity of novel DosR regulon-encoded candidate antigens of Mycobacterium tuberculosis in three high-burden populations in Africa. Clin Vaccine Immunol. 2009;16:1203–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nooshabadi F, Yang HJ, Cheng Y, Durkee MS, Xie H, Rao J, Cirillo JD, Maitland KC. Intravital excitation increases detection sensitivity for pulmonary tuberculosis by whole-body imaging with beta-lactamase reporter enzyme fluorescence. J Biophotonics. 2016;10(6–7):821–9.

    PubMed  PubMed Central  Google Scholar 

  104. Sutherland JS, Lalor MK, Black GF, Ambrose LR, Loxton AG, Chegou NN, Kassa D, Mihret A, Howe R, Mayanja-Kizza H, Gomez MP, Donkor S, Franken K, Hanekom W, Klein MR, Parida SK, Boom WH, Thiel BA, Crampin AC, Ota M, Walzl G, Ottenhoff TH, Dockrell HM, Kaufmann SH, GCGH Biomarkers for TB consortium. Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa. PLoS One. 2013;8:e74080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Adekambi T, Ibegbu CC, Cagle S, Kalokhe AS, Wang YF, Hu Y, Day CL, Ray SM, Rengarajan J. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J Clin Invest. 2015;125:1827–38.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Adekambi T, Ibegbu CC, Kalokhe AS, Yu T, Ray SM, Rengarajan J. Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, Bcg vaccination and clinically resolved tuberculosis. PLoS One. 2012;7:e36046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Schuetz A, Haule A, Reither K, Ngwenyama N, Rachow A, Meyerhans A, Maboko L, Koup RA, Hoelscher M, Geldmacher C. Monitoring CD27 expression to evaluate Mycobacterium tuberculosis activity in HIV-1 infected individuals in vivo. PLoS One. 2011;6:e27284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chegou NN, Black GF, Loxton AG, Stanley K, Essone PN, Klein MR, Parida SK, Kaufmann SH, Doherty TM, Friggen AH, Franken KL, Ottenhoff TH, Walzl G. Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of Tb disease in a high burden setting. BMC Infect Dis. 2012;12:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chegou NN, Essone PN, Loxton AG, Stanley K, Black GF, Van Der Spuy GD, Van Helden PD, Franken KL, Parida SK, Klein MR, Kaufmann SH, Ottenhoff TH, Walzl G. Potential of host markers produced by infection phase-dependent antigen-stimulated cells for the diagnosis of tuberculosis in a highly endemic area. PLoS One. 2012;7:e38501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kimuda SG, Nalwoga A, Levin J, Franken KL, Ottenhoff TH, Elliott AM, Cose S, Andia-Biraro I. Humoral responses to Rv1733c, Rv0081, Rv1735c, and Rv1737c DosR Regulon-encoded proteins of Mycobacterium tuberculosis in individuals with latent tuberculosis infection. J Immunol Res. 2017;2017:1593143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Leyten EM, Lin MY, Franken KL, Friggen AH, Prins C, Van Meijgaarden KE, Voskuil MI, Weldingh K, Andersen P, Schoolnik GK, Arend SM, Ottenhoff TH, Klein MR. Human T-cell responses to 25 novel antigens encoded by genes of the dormancy regulon of Mycobacterium tuberculosis. Microbes Infect. 2006;8:2052–60.

    Article  CAS  PubMed  Google Scholar 

  112. Lin MY, Geluk A, Smith SG, Stewart AL, Friggen AH, Franken KL, Verduyn MJ, Van Meijgaarden KE, Voskuil MI, Dockrell HM, Huygen K, Ottenhoff TH, Klein MR. Lack of immune responses to Mycobacterium tuberculosis DosR regulon proteins following Mycobacterium bovis BCG vaccination. Infect Immun. 2007;75:3523–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Slavin RE, Walsh TJ, Pollack AD. Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine (Baltimore). 1980;59:352–66.

    Article  CAS  Google Scholar 

  114. Horsburgh CR, O’donnell M, Chamblee S, Moreland JL, Johnson J, Marsh BJ, Narita M, Johnson LS, Von Reyn CF. Revisiting rates of reactivation tuberculosis. Am J Respir Crit Care Med. 2010;182:420–5.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Anderson ST, Kaforou M, Brent AJ, Wright VJ, Banwell CM, Chagaluka G, Crampin AC, Dockrell HM, French N, Hamilton MS, Hibberd ML, Kern F, Langford PR, Ling L, Mlotha R, Ottenhoff THM, Pienaar S, Pillay V, Scott JAG, Twahir H, Wilkinson RJ, Coin LJ, Heyderman RS, Levin M, Eley B. Diagnosis of childhood tuberculosis and host Rna expression in Africa. N Engl J Med. 2014;370:1712–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Escalante P, Peikert T, Van Keulen VP, Erskine CL, Bornhorst CL, Andrist BR, McCoy K, Pease LR, Abraham RS, Knutson KL, Kita H, Schrum AG, Limper AH. Combinatorial immunoprofiling in latent tuberculosis infection. Toward better risk stratification. Am J Respir Crit Care Med. 2015;192:605–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kaforou M, Wright VJ, Oni T, French N, Anderson ST, Bangani N, Banwell CM, Brent AJ, Crampin AC, Dockrell HM, Eley B, Heyderman RS, Hibberd ML, Kern F, Langford PR, Ling L, Mendelson M, Ottenhoff TH, Zgambo F, Wilkinson RJ, Coin LJ, Levin M. Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study. PLoS Med. 2013;10:e1001538.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zak D, Scriba TJ, Hatherill M, Penn-Nicholson A, Hanekom W. Predicting tuberculosis risk – Authors’ reply. Lancet. 2016;388:2233–4.

    Article  PubMed  Google Scholar 

  119. Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, Mahomed H, Erasmus M, Whatney W, Hussey GD, Abrahams D, Kafaar F, Hawkridge T, Verver S, Hughes EJ, Ota M, Sutherland J, Howe R, Dockrell HM, Boom WH, Thiel B, Ottenhoff TH, Mayanja-Kizza H, Crampin AC, Downing K, Hatherill M, Valvo J, Shankar S, Parida SK, Kaufmann SH, Walzl G, Aderem A, Hanekom WA, ACS and GC6-74 cohort study groups. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016;387:2312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schubert OT, Ludwig C, Kogadeeva M, Zimmermann M, Rosenberger G, Gengenbacher M, Gillet LC, Collins BC, Rost HL, Kaufmann SH, Sauer U, Aebersold R. Absolute proteome composition and dynamics during dormancy and resuscitation of Mycobacterium tuberculosis. Cell Host Microbe. 2015;18:96–108.

    Article  CAS  PubMed  Google Scholar 

  121. Semu M, Fenta TG, Medhin G, Assefa D. Effectiveness of isoniazid preventative therapy in reducing incidence of active tuberculosis among people living with HIV/AIDS in public health facilities of Addis Ababa, Ethiopia: a historical cohort study. BMC Infect Dis. 2017;17:5.

    Article  PubMed  PubMed Central  Google Scholar 

  122. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ. 1982;60:555–64.

    PubMed Central  Google Scholar 

  123. Ai JW, Ruan QL, Liu QH, Zhang WH. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerg Microbes Infect. 2016;5:e10.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis. 1967;95:935–43.

    CAS  PubMed  Google Scholar 

  125. Ferebee SH. Long-term effects of isoniazid prophylaxis. Bull Int Union Tuberc. 1968;41:161–6.

    CAS  PubMed  Google Scholar 

  126. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc. 1970;26:28–106.

    CAS  PubMed  Google Scholar 

  127. Churchyard GJ, Fielding KL, Grant AD. A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med. 2014;370:1662–3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Raul Barletta for critical review of the manuscript.

Funding

NIH, NIAID provided funding to Jeffrey D. Cirillo under grant number R01AI104960.

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  1. Department of Microbial Pathogenesis and Immunology, Texas A&M University College of Medicine, Bryan, TX, USA

    Parnia Behinaein & Jeffrey D. Cirillo

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  1. Parnia Behinaein
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Correspondence to Jeffrey D. Cirillo .

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  1. Department of Microbial Pathogenesis and Immunology, Texas A&M University College of Medicine, Bryan, TX, USA

    Jeffrey D. Cirillo

  2. The University of Tennessee Health Science Center, Memphis, TN, USA

    Ying Kong

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Behinaein, P., Cirillo, J.D. (2019). The Silent Plague: Regulation of Latent Tuberculosis Infections. In: Cirillo, J., Kong, Y. (eds) Tuberculosis Host-Pathogen Interactions. Springer, Cham. https://doi.org/10.1007/978-3-030-25381-3_2

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