Skip to main content
Virologica Sinica logoLink to Virologica Sinica
. 2015 Jan 13;30(1):3–10. doi: 10.1007/s12250-014-3547-2

Bacteriophage secondary infection

Stephen T Abedon 1,
PMCID: PMC8200926  PMID: 25595214

Abstract

Phages are credited with having been first described in what we now, officially, are commemorating as the 100th anniversary of their discovery. Those one-hundred years of phage history have not been lacking in excitement, controversy, and occasional convolution. One such complication is the concept of secondary infection, which can take on multiple forms with myriad consequences. The terms secondary infection and secondary adsorption, for example, can be used almost synonymously to describe virion interaction with already phage-infected bacteria, and which can result in what are described as superinfection exclusion or superinfection immunity. The phrase secondary infection also may be used equivalently to superinfection or coinfection, with each of these terms borrowed from medical microbiology, and can result in genetic exchange between phages, phage-on-phage parasitism, and various partial reductions in phage productivity that have been termed mutual exclusion, partial exclusion, or the depressor effect. Alternatively, and drawing from epidemiology, secondary infection has been used to describe phage population growth as that can occur during active phage therapy as well as upon phage contamination of industrial ferments. Here primary infections represent initial bacterial population exposure to phages while consequent phage replication can lead to additional, that is, secondary infections of what otherwise are not yet phage-infected bacteria. Here I explore the varying meanings and resultant ambiguity that has been associated with the term secondary infection. I suggest in particular that secondary infection, as distinctly different phenomena, can in multiple ways influence the success of phage-mediated biocontrol of bacteria, also known as, phage therapy.

Keywords: lysis from without, lysis inhibition, coinfection, parallel secondary infection, phage therapy, pharmacology, serial secondary infection, superinfection

References

  1. Abedon S. Phage therapy pharmacology: calculating phage dosing. Adv Appl Microbiol. 2011;77:10–40. doi: 10.1016/B978-0-12-387044-5.00001-7. [DOI] [PubMed] [Google Scholar]
  2. Abedon S T. Selection for lysis inhibition in bacteriophage. J Theor Biol. 1990;146:501–511. doi: 10.1016/S0022-5193(05)80375-3. [DOI] [PubMed] [Google Scholar]
  3. Abedon S T. Lysis of lysis inhibited bacteriophage T4-infected cells. J Bacteriol. 1992;174:8073–8080. doi: 10.1128/jb.174.24.8073-8080.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Abedon S T. Lysis and the interaction between free phages and infected cells. In: Karam J D, Kutter E, Carlson K, Guttman B, editors. The Molecular Biology of Bacteriophage T4. Washington DC: ASM Press; 1994. pp. 397–405. [Google Scholar]
  5. Abedon S T. Bacteriophage T4 resistance to lysis-inhibition collapse. Genet Res. 1999;74:1–11. doi: 10.1017/S0016672399003833. [DOI] [PubMed] [Google Scholar]
  6. Abedon S T. Phage population growth: constraints, games, adaptation. In: Abedon ST, editor. Bacteriophage Ecology. Cambridge: Cambridge University Press; 2008. pp. 64–93. [Google Scholar]
  7. Abedon S T. Bacteriophage intraspecific cooperation and defection. In: Adams H T, editor. Contemporary Trends in Bacteriophage Research. Hauppauge: Nova Science Publishers; 2009. pp. 191–215. [Google Scholar]
  8. Abedon S T. Disambiguating bacteriophage pseudolysogeny: an historical analysis of lysogeny, pseudolysogeny, and the phage carrier state. In: Adams H T, editor. Contemporary Trends in Bacteriophage Research. Hauppauge: Nova Science Publishers; 2009. pp. 285–307. [Google Scholar]
  9. Abedon S T. Kinetics of phage-mediated biocontrol of bacteria. Foodborne Pathog Dis. 2009;6:807–815. doi: 10.1089/fpd.2008.0242. [DOI] [PubMed] [Google Scholar]
  10. Abedon S T. Bacteriophages and Biofilms: Ecology, Phage Therapy, Plaques. Hauppauge: Nova Science Publishers; 2011. [Google Scholar]
  11. Abedon S T. Lysis from without. Bacteriophage. 2011;1:46–49. doi: 10.4161/bact.1.1.13980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Abedon S T. Phage therapy best practices. In: Hyman P, Abedon S T, editors. Bacteriophages in Health and Disease. Wallingford: CABI Press; 2012. pp. 256–272. [Google Scholar]
  13. Abedon ST. Spatial vulnerability: bacterial arrangements, microcolonies, and biofilms as responses to low rather than high phage densities. Viruses. 2012;4:663–687. doi: 10.3390/v4050663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Abedon ST. Thinking about microcolonies as phage targets. Bacteriophage. 2012;2:200–204. doi: 10.4161/bact.22444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Abedon ST. Bacteriophages as drugs: the pharmacology of phage therapy. In: Borysowski J, Miedzybrodzki R, Górski A, editors. Phage Therapy: Current Research and Applications. Norfolk: Caister Academic Press; 2014. pp. 69–100. [Google Scholar]
  16. Abedon S T, Kuhl S J, Blasdel B G, Kutter E M. Phage treatment of human infections. Bacteriophage. 2011;1:66–85. doi: 10.4161/bact.1.2.15845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Abedon S T, Thomas-Abedon C. Phage therapy pharmacology. Curr Pharm Biotechnol. 2010;11:28–47. doi: 10.2174/138920110790725410. [DOI] [PubMed] [Google Scholar]
  18. Adams M H. Bacteriophages. New York: InterScience; 1959. [Google Scholar]
  19. Barron B A, Fischetti V A, Zabriskie J B. Studies of the bacteriophage kinetics of multicellular systems: a statistical model for the estimation of burst size per cell in streptococci. J Appl Bacteriol. 1970;33:436–442. doi: 10.1111/j.1365-2672.1970.tb02216.x. [DOI] [PubMed] [Google Scholar]
  20. Benzer S, Hudson W, Weidel W, Delbruck M, Stent G S, Weigle J J, Dulbecco R, Watson J D, Wollman E L. 1950. A syllabus on procedures, facts, and interpretations in phage. Viruses 1950. Delbruck M (ed). Pasadena: California Institute of Technology, pp100–147.
  21. Berngruber T W, Weissing F J, Gandon S. Superinfection inhibition and the evolution of viral latency. J Virol. 2010;84:10200–10208. doi: 10.1128/JVI.00865-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Bigwood T, Hudson J A, Billington C. Influence of host and bacteriophage concentrations on the inactivation of foodborne pathogenic bacteria by two phages. FEMS Microbiol Lett. 2009;291:59–64. doi: 10.1111/j.1574-6968.2008.01435.x. [DOI] [PubMed] [Google Scholar]
  23. Bull J J, Regoes R R. Pharmacodynamics of non-replicating viruses, bacteriocins and lysins. Proc R Soc Lond B Biol Sci. 2006;273:2703–2712. doi: 10.1098/rspb.2006.3640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Chan B K, Abedon S T. Phage therapy pharmacology: phage cocktails. Adv Appl Microbiol. 2012;78:1–23. doi: 10.1016/B978-0-12-394805-2.00001-4. [DOI] [PubMed] [Google Scholar]
  25. Chan B K, Abedon S T, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol. 2013;8:769–783. doi: 10.2217/fmb.13.47. [DOI] [PubMed] [Google Scholar]
  26. Davis B M, Kimsey H H, Chang W, Waldor M K. The Vibrio cholerae O139 Calcutta bacteriophage CTXϕ is infectious and encodes a novel repressor. J Bacteriol. 1999;181:6779–6787. doi: 10.1128/jb.181.21.6779-6787.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Doermann A H. Lysis and lysis inhibition with Escherichia coli bacteriophage. J Bacteriol. 1948;55:257–275. doi: 10.1128/jb.55.2.257-276.1948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Espeland E M, Lipp E K, Huq A, Colwell R R. Polylysogeny and prophage induction by secondary infection in Vibrio cholerae. Environ Microbiol. 2004;6:760–763. doi: 10.1111/j.1462-2920.2004.00603.x. [DOI] [PubMed] [Google Scholar]
  29. Fogg P C, Allison H E, Saunders J R, McCarthy A J. Bacteriophage lambda: a paradigm revisited. J Virol. 2010;84:6876–6879. doi: 10.1128/JVI.02177-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Fogg P C M, Gossage S M, Smith D L, Saunders J R, McCarthy A J, Allison H E. Identification of multiple integration sites for Stx-phage Φ24B in the Escherichia coli genome, description of a novel integrase and evidence for a functional anti-repressor. Microbiology. 2007;153:4098–4110. doi: 10.1099/mic.0.2007/011205-0. [DOI] [PubMed] [Google Scholar]
  31. French R C, Graham A F, Lesley S M, van Rooyen C E. The contribution of phosphorus from T2r+ bacteriophage to progeny. J Bacteriol. 1952;64:597–607. doi: 10.1128/jb.64.5.597-607.1952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Fukuda E, Kaminska K H, Bujnicki J M, Kobayashi I. Cell death upon epigenetic genome methylation: a novel function of methyl-specific deoxyribonucleases. Genome Biol. 2008;9:R163. doi: 10.1186/gb-2008-9-11-r163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Golshahi L, Seed K D, Dennis J J, Finlay W H. Toward modern inhalational bacteriophage therapy: nebulization of bacteriophages of Burkholderia cepacia complex. J Aerosol Med Pulm Drug Deliv. 2008;21:351–360. doi: 10.1089/jamp.2008.0701. [DOI] [PubMed] [Google Scholar]
  34. Hatfull G F, Hendrix R W. Bacteriophages and their genomes. Curr Opin Virol. 2011;1:298–303. doi: 10.1016/j.coviro.2011.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hendrix R W. Phage evolution. In: Abedon ST, editor. Bacteriophage Ecology. Cambridge: Cambridge University Press; 2008. pp. 177–194. [Google Scholar]
  36. Hendrix R W, Smith M C M, Burns R N, Ford M E, Hatfull G F. Evolutionary relationships among diverse bacteriophages and prophages: All the world’s a phage. Proc Natl Acad Sci USA. 1999;96:2192–2197. doi: 10.1073/pnas.96.5.2192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hudson J A, Billington C, Carey-Smith G, Greening G. Bacteriophages as biocontrol agents in food. J Food Prot. 2005;68:426–437. doi: 10.4315/0362-028x-68.2.426. [DOI] [PubMed] [Google Scholar]
  38. Hughes K A, Sutherland I W, Jones M V. Biofilm susceptibility to bacteriophage attack: the role of phage-borne polysac charide depolymerase. Microbiology. 1998;144:3039–3047. doi: 10.1099/00221287-144-11-3039. [DOI] [PubMed] [Google Scholar]
  39. Hyman P, Abedon S T. Bacteriophage host range and bacterial resistance. Adv Appl Microbiol. 2010;70:217–248. doi: 10.1016/S0065-2164(10)70007-1. [DOI] [PubMed] [Google Scholar]
  40. Hyman P, Abedon S T. Smaller fleas: viruses of microorganisms. Scientifica. 2012;2012:734023. doi: 10.6064/2012/734023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Iyer V N, James A P. Single-cell studies on the carrier state of bacteriophage IKe, a virus specific for conjugative plasmids of the N incompatibility and conjugative group. Can J Microbiol. 1978;24:1595–1601. doi: 10.1139/m78-255. [DOI] [PubMed] [Google Scholar]
  42. Mann N H. Phages of the marine cyanobacterial picophytoplankton. FEMS Microbiol Rev. 2003;27:17–34. doi: 10.1016/S0168-6445(03)00016-0. [DOI] [PubMed] [Google Scholar]
  43. May R M, Anderson R M. Parasite-host coevolution. In: Futuyma D J, Slatkin M, editors. Coevolution. Sunderland: Sinauer Associates; 1983. pp. 186–206. [Google Scholar]
  44. Moussa S H, Kuznetsov V, Tran T A, Sacchettini J C, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012;21:571–582. doi: 10.1002/pro.2042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Moussa S H, Lawler J L, Young R. Genetic dissection of T4 lysis. J Bacteriol. 2014;196:2201–2209. doi: 10.1128/JB.01548-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Payne R J H, Jansen V A A. Understanding bacteriophage therapy as a density-dependent kinetic process. J Theor Biol. 2001;208:37–48. doi: 10.1006/jtbi.2000.2198. [DOI] [PubMed] [Google Scholar]
  47. Payne R J H, Jansen V A A. Pharmacokinetic principles of bacteriophage therapy. Clin Pharmacokinet. 2003;42:315–325. doi: 10.2165/00003088-200342040-00002. [DOI] [PubMed] [Google Scholar]
  48. Payne R J H, Phil D, Jansen V A A. Phage therapy: The peculiar kinetics of self-replicating pharmaceuticals. Clin Pharmacol Ther. 2000;68:225–230. doi: 10.1067/mcp.2000.109520. [DOI] [PubMed] [Google Scholar]
  49. Pratt J H. Secondary infection of the skin and subcutaneous tissues by the bacillus typhosus. J Boston Soc Med Sci. 1899;3:170–173. [PMC free article] [PubMed] [Google Scholar]
  50. Ryan E M, Gorman S P, Donnelly R F, Gilmore B F. Recent advances in bacteriophage therapy: how delivery routes, formulation, concentration and timing influence the success of phage therapy. J Pharm Pharamcol. 2011;63:1253–1264. doi: 10.1111/j.2042-7158.2011.01324.x. [DOI] [PubMed] [Google Scholar]
  51. Sanders M E. Bacteriophages of industrial importance. In: Goyal S M, Gerba G P, Bitton G, editors. Phage Ecology. New York: John Wiley & Sons; 1987. pp. 211–244. [Google Scholar]
  52. Slavcev R A, Hayes S. Rex-centric mutualism. J Bacteriol. 2002;184:857–858. doi: 10.1128/JB.184.3.857-858.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Smith D L, Rooks D J, Fogg P C, Darby A C, Thomson N R, Mc-Carthy A J, Allison H E. Comparative genomics of Shiga toxin encoding bacteriophages. BMC Genomics. 2012;13:311. doi: 10.1186/1471-2164-13-311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stent G S. Molecular biology of bacterial viruses. San Francisco: WH Freeman and Co; 1963. [Google Scholar]
  55. Sturino J M, Klaenhammer T R. Engineered bacteriophage-defence systems in bioprocessing. Nat Rev Microbiol. 2006;4:395–404. doi: 10.1038/nrmicro1393. [DOI] [PubMed] [Google Scholar]
  56. Tran T A, Struck D K, Young R. Periplasmic domains define holin-antiholin interactions in T4 lysis inhibition. J Bacteriol. 2005;187:6631–6640. doi: 10.1128/JB.187.19.6631-6640.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tran T A, Struck D K, Young R. The T4 RI antiholin has an N-terminal signal anchor release domain that targets it for degradation by DegP. J Bacteriol. 2007;189:7618–7625. doi: 10.1128/JB.00854-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Turner P E, Duffy S. Evolutionary ecology of multi-phage infections. In: Abedon ST, editor. Bacteriophage Ecology. Cambridge: Cambridge University Press; 2008. pp. 195–216. [Google Scholar]
  59. Wei W, Krone S M. Spatial invasion by a mutant pathogen. J Theor Biol. 2005;236:335–348. doi: 10.1016/j.jtbi.2005.03.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Weinfeld H, Paigen K. Evidence for a new intermediate state of the viral chromosome during cooperative infection by host-modified lambda phage. Virology. 1964;24:71–83. doi: 10.1016/0042-6822(64)90149-7. [DOI] [PubMed] [Google Scholar]
  61. Werner E R, Christensen J R. Infection by bacteriophage P1 and development of host-controlled restriction and modification and of lysogenic immunity. J Virol. 1969;3:363–368. doi: 10.1128/jvi.3.4.363-368.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Yamada T, Kawasaki T, Nagata S, Fujiwara A, Usami S, Fujie M. New bacteriophages that infect the phytopathogen Ralstonia solanacearum. Microbiology. 2007;153:2630–2639. doi: 10.1099/mic.0.2006/001453-0. [DOI] [PubMed] [Google Scholar]

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES