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Persister cells

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Persister cells are subpopulations of cells that resist treatment, and become antimicrobial tolerant by changing to a state of dormancy or quiescence.[1][2] Persister cells in their dormancy do not divide.[3] The tolerance shown in persister cells differs from antimicrobial resistance in that the tolerance is not inherited and is reversible.[4] When treatment has stopped the state of dormancy can be reversed and the cells can reactivate and multiply. Most persister cells are bacterial, and there are also fungal persister cells,[5] yeast persister cells, and cancer persister cells that show tolerance for cancer drugs.[6]

History

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Recognition of bacterial persister cells dates back to 1944 when Joseph Warwick Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculate a culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic exposure. The important observation that Bigger made was that this new population could again be almost eliminated by the use of penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’.[7] The formation of bacterial persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment[8] or in response to a variety of antibiotics.[9]

Relevance to chronic infections

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Antimicrobial tolerance is achieved by a small subpopulation of microbial cells termed persisters.[7] Persisters are not mutants, but rather are dormant cells that can survive the antimicrobials that effectively eliminate their much greater number. Persister cells have entered a non-growing, or extremely slow-growing physiological state which makes them tolerant (insensitive or refractory) to the action of antimicrobials. When such persisting pathogenic microbes cannot be eliminated by the immune system, they become a reservoir from which recurrence of infection will develop.[10] Such non-growing bacteria have been observed to persist during infections from Salmonella.[11] Persister cells are the main cause of relapsing and chronic infections.[2][5]

The bacteria species Listeria monocytogenes, the main causal agent of listeriosis, has been shown to demonstrate persistence during infection in hepatocyte and trophoblast cells. The usual active lifestyle can change and the bacteria can remain in intracellular vacuoles entering into a slow non-growing state of persistence thus promoting their survival from antibiotics.[12]

Fungal persister cells are a common cause of recurring infections due to Candida albicans a common biofilm infection of implants.[5]

Medical importance

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Further information: Biofilm § In medicine

Antibiotic tolerance poses medically important challenges. It is largely responsible for the inability to eradicate bacterial infections with antibiotic treatment. Persister cells are highly enriched in biofilms, and this makes biofilm-related diseases difficult to treat. Examples are chronic infections of implanted medical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease.[13]

Resistance vs tolerance

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Unlike multiple drug resistance, and antimicrobial resistance, antimicrobial tolerance is transient, and not inherited.[2][7][10] Antibiotic tolerant persister cells are not antibiotic resistant mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer) that are heritable and confer the ability to grow at elevated concentrations of antibiotics. In contrast, tolerant bacteria have the same minimum inhibitory concentration (MIC) as susceptible bacteria,[3] and differ in the duration of the treatment that they can survive. Antibiotic tolerance can be caused by a reversible physiological state in a small subpopulation of genetically identical cells,[2][7][10] similar to a differentiated cell type.[14] It enables this small subpopulation of bacteria to survive their complete elimination by antibiotic use. Persisting cells resume growth when the antibiotic is removed, and their progeny is sensitive to antibiotics.[2][7][10]

Molecular mechanisms

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The molecular mechanisms that underlie persister cell formation, and antimicrobial tolerance are largely unknown.[2][10] Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch,[10][4] although inducible mechanisms of persister cell formation have been described.[10][15] For instance, toxin-antitoxin systems,[16] and a number of different stress responses such as the SOS response,[15] the envelope stress response,[17] and the starvation response have also been associated with persister cell formation in biofilms.[18] Owing to their transient nature and relatively low abundance, it is hard to isolate persister cells in sufficient numbers for experimental characterization, and only a few relevant genes have been identified to date.[2][10] The best-understood persistence factor is the E. coli high persistence gene, commonly abbreviated as hipA.[19]

Although tolerance is widely considered a passive state, there is evidence indicating it can be an energy-dependent process.[20] Persister cells in E. coli can transport intracellular accumulations antibiotic using an energy requiring efflux pump called TolC.[21]

A persister subpopulation has also been demonstrated in budding yeast Saccharomyces cerevisiae. Yeast persisters are triggered in a small subset of unperturbed exponentially growing cells by spontaneously occurring DNA damage, which leads to the activation of a general stress response and protection against a range of harsh drug and stress environments. As a result of the DNA damage, yeast persisters are also enriched for random genetic mutations that occurred prior to the stress, and are unrelated to the stress survival.[22]

In response to antifungals, fungal persister cells activate stress-response pathways, and two stress-protective molecules – glycogen, and trehalose accumulate in large amounts.[5]

Potential treatment

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A study has shown that adding certain metabolites to aminoglycosides could enable bacterial persisters to be eliminated. This study was carried out on a number of bacterial species including E. coli and S. aureus.[23]

Phage therapy, where applicable, is thought to entirely circumvent antibiotic tolerance,[24][25] though phages themselves may be capable of inducing the persister state.[26]

See also

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References

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  1. ^ Van den Bergh, B; Fauvart, M; Michiels, J (1 May 2017). "Formation, physiology, ecology, evolution and clinical importance of bacterial persisters". FEMS Microbiology Reviews. 41 (3): 219–251. doi:10.1093/femsre/fux001. PMID 28333307.
  2. ^ a b c d e f g Lewis K (2007). "Persister cells, dormancy and infectious disease". Nature Reviews Microbiology. 5 (1): 48–56. doi:10.1038/nrmicro1557. PMID 17143318. S2CID 6670040.
  3. ^ a b Brauner, A (2017). "Distinguishing between resistance, tolerance and persistence to antibiotic treatment". Nature Reviews Microbiology. 14 (5): 320–30. doi:10.1038/nrmicro.2016.34. PMID 27080241. S2CID 8308100.
  4. ^ a b Jayaraman, R (December 2008). "Bacterial persistence: some new insights into an old phenomenon". Journal of Biosciences. 33 (5): 795–805. doi:10.1007/s12038-008-0099-3. PMID 19179767. S2CID 31912576.
  5. ^ a b c d Wuyts, J; Van Dijck, P; Holtappels, M (October 2018). "Fungal persister cells: The basis for recalcitrant infections?". PLOS Pathogens. 14 (10): e1007301. doi:10.1371/journal.ppat.1007301. PMC 6193731. PMID 30335865.
  6. ^ Vallette, FM (April 2019). "Dormant, quiescent, tolerant and persister cells: Four synonyms for the same target in cancer" (PDF). Biochemical Pharmacology. 162: 169–176. doi:10.1016/j.bcp.2018.11.004. PMID 30414937. S2CID 53285399.
  7. ^ a b c d e Bigger JW (14 October 1944). "Treatment of staphylococcal infections with penicllin by intermittent sterilization". Lancet. 244 (6320): 497–500. doi:10.1016/S0140-6736(00)74210-3.
  8. ^ Balaban, NQ (2004). "Bacterial persistence as a phenotypic switch". Science. 305 (5690): 1622–5. Bibcode:2004Sci...305.1622B. doi:10.1126/science.1099390. PMID 15308767. S2CID 39698842.
  9. ^ Lewis, K (2010). "Persister cells". Annual Review of Microbiology. 64: 357–72. doi:10.1146/annurev.micro.112408.134306. PMID 20528688.
  10. ^ a b c d e f g h Gefen O, Balaban NQ (July 2009). "The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress". FEMS Microbiol. Rev. 33 (4): 704–17. doi:10.1111/j.1574-6976.2008.00156.x. PMID 19207742.
  11. ^ Helaine, Sophie (2014). "Internalization of Salmonella by macrophages induces formation of nonreplicating persisters". Science. 343 (6167): 204–8. Bibcode:2014Sci...343..204H. doi:10.1126/science.1244705. PMC 6485627. PMID 24408438.
  12. ^ Kortebi, M; Milohanic, E; Mitchell, G (November 2017). "Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells". PLOS Pathogens. 13 (11): e1006734. doi:10.1371/journal.ppat.1006734. PMC 5708623. PMID 29190284.
  13. ^ Khatoon, Zohra; McTiernan, Christopher D.; Suuronen, Erik J.; Mah, Thien-Fah; Alarcon, Emilio I. (2018). "Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention". Heliyon. 4 (12): e01067. Bibcode:2018Heliy...401067K. doi:10.1016/j.heliyon.2018.e01067. ISSN 2405-8440. PMC 6312881. PMID 30619958.
  14. ^ Lopez D, Vlamakis H, Kolter R (January 2009). "Generation of multiple cell types in Bacillus subtilis". FEMS Microbiol Rev. 33 (1): 152–63. doi:10.1111/j.1574-6976.2008.00148.x. PMID 19054118.
  15. ^ a b Dörr T, Lewis K, Vulic M (2009). Rosenberg SM (ed.). "SOS Response Induces Persistence to Fluoroquinolones in Escherichia coli". PLOS Genet. 5 (12): e1000760. doi:10.1371/journal.pgen.1000760. PMC 2780357. PMID 20011100.
  16. ^ Wang, Xiaoxue; Wood, Thomas K. (2011-08-15). "Toxin-Antitoxin Systems Influence Biofilm and Persister Cell Formation and the General Stress Response". Applied and Environmental Microbiology. 77 (16): 5577–5583. Bibcode:2011ApEnM..77.5577W. doi:10.1128/AEM.05068-11. ISSN 0099-2240. PMC 3165247. PMID 21685157.
  17. ^ Kan, Tanaka; Hideo, Takahashi (December 1994). "Cloning, analysis and expression of an rpoS homologue gene from Pseudomonas aeruginosa PAO1". Gene. 150 (1): 81–85. doi:10.1016/0378-1119(94)90862-1. ISSN 0378-1119. PMID 7959068.
  18. ^ Fux, C.A.; Costerton, J.W.; Stewart, P.S.; Stoodley, P. (January 2005). "Survival strategies of infectious biofilms". Trends in Microbiology. 13 (1): 34–40. doi:10.1016/j.tim.2004.11.010. PMID 15639630. S2CID 10216159.
  19. ^ Moyed HS, Bertrand KP (1983). "hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis". J. Bacteriol. 155 (2): 768–75. doi:10.1128/JB.155.2.768-775.1983. PMC 217749. PMID 6348026.
  20. ^ Harms, Alexander; Maisonneuve, Etienne; Gerdes, Kenn (2016). "Mechanisms of bacterial persistence during stress and antibiotic exposure". Science. 354 (6318): aaf4268. doi:10.1126/science.aaf4268. PMID 27980159. S2CID 39255372.
  21. ^ Pu, Y.; et al. (2016). "Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells". Mol Cell. 62 (2): 284–294. doi:10.1016/j.molcel.2016.03.035. PMC 4850422. PMID 27105118.
  22. ^ Yaakov, G.; Lerner, D.; Bentele, K.; Steinberger, J.; Barkai, N. (2017). "Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress". Nature Ecology & Evolution. 1 (1): 16. Bibcode:2017NatEE...1...16Y. doi:10.1038/s41559-016-0016. PMID 28812556. S2CID 15812250.
  23. ^ Allison KR, Brynildsen MP, Collins JJ (2011). "Metabolite-enabled eradication of bacterial persisters by aminoglycosides". Nature. 473 (7346): 216–220. Bibcode:2011Natur.473..216A. doi:10.1038/nature10069. PMC 3145328. PMID 21562562.
  24. ^ Loganathan, Archana; Manohar, Prasanth; Eniyan, Kandasamy; VinodKumar, C. S.; Leptihn, Sebastian; Nachimuthu, Ramesh (2021-08-28). "Phage therapy as a revolutionary medicine against Gram-positive bacterial infections". Beni-Suef University Journal of Basic and Applied Sciences. 10 (1): 49. doi:10.1186/s43088-021-00141-8. ISSN 2314-8543. PMC 8401357. PMID 34485539.
  25. ^ Vera-Mansilla, Javiera; Silva-Valenzuela, Cecilia A.; Sánchez, Patricio; Molina-Quiroz, Roberto C. (2023-09-01). "Bacteriophages potentiate the effect of antibiotics by eradication of persister cells and killing of biofilm-forming cells". Research in Microbiology. 174 (7): 104083. doi:10.1016/j.resmic.2023.104083. ISSN 0923-2508. PMID 37257734.
  26. ^ Sanchez-Torres V, Kirigo J, Wood TK (2024). "Implications of lytic phage infections inducing persistence". Current Opinion in Microbiology. 79: 102482. doi:10.1016/j.mib.2024.102482. PMID 38714140.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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