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Human Virome

SOVREMENNAYA PEDIATRIYA.2019.1(97):49-74; doi 10.15574/SP.2019.97.49

Yankovsky D. S., Dyment G. S., Berezhnoy V. V., Kitam V. O., Khimich N. V.
Science production company «O.D. Prolisok», Kyiv, Ukraine

The review is dealt with virome, a viral component of human microbiome. Modern data are discussed that concern the structure of virome, its formation during ontogenesis, the role in disease pathogeneses and in homeostasis maintenance. Special attention is payed to bacteriophages (phagobiome) as dominant members of virome. Modern data are submitted about the influence of bacteriophages on the state of microbiome prokaryotic community, immune system and their potential participation in the development of pathologies. Controversial questions, connected with the perspective of using bacteriophage therapy in medicine, are considered.

Key words: virome, microbiome, viruses, bacteriophages, metagenomics, prokaryotes, phagobiome, phage therapy.


1. Bobyr VV, Poniatovskiy VA, Diuzhikova OM, Shirobokov VP. (2015). New data on human virome and influence of microbiota on its functioning. Visnyk morfologii. 21; 2: 531-537.

2. Umanskiy GK. (1979). Virus presumption of innocence. Khimia i zhizn’. 5: 25-29.

3. Yankovskiy DS, Shirobokov VP, Dyment GS. (2017). Microbiome. Kiev: FLP Veres O.I.: 640.

4. Abedon ST. (2015). Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages. Pharmaceuticals (Basel). 8: 525–558.

5. Abeles SR, Robles-Sikisaka R, Ly M, Lum AG, Salzman J, Boehm TK, Pride DT. (2014). Human oral viruses are personal, persistent and gender-consistent. ISME J. 8(9): 1753–1767. Epub 2014 Mar 20.

6. Abeles SR, Pride DT. (2014). Molecular bases and role of viruses in the human microbiome. J Mol Biol. 426: 3892–3906. Epub 2014 Jul 11.

7. Abeles SR, Ly M, Santiago-Rodriguez TM, Pride DT. (2015). Effects of Long Term Antibiotic Therapy on Human Oral and Fecal Viromes. PLOS ONE. 10:e0134941.

8. Abeles SR, Jones MB, Santiago-Rodriguez TM, Ly M, Klitgord N, Yooseph S, Nelson KE, Pride DT. (2016). Microbial diversity in individuals and their household contacts following typical antibiotic courses. Microbiome. 4(1): 39.

9. Asadulghani M, Ogura Y, Ooka T, Itoh T, Sawaguchi A, Iguchi A et al. (2009). The defective prophage pool of Escherichia coli O157: prophage-prophage interactions potentiate horizontal transfer of virulence determinants. PLoS Pathog. 5: e1000408.

10. Asano Y, Hiramoto T, Nishino R, Aiba Y, Kimura T, Yoshihara K, Koga Y, Sudo N. (2012). Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 303: 1288–1295. Epub 2012 Oct 11.

11. Ayukekbong J, Lindh M, Nenonen N, Tah F, Nkuo-Akenji T, Bergstrom T. (2011). Enteric viruses in healthy children in Cameroon: viral load and genotyping of norovirus strains. J. Med. Virol. 83: 2135–2142.

12. Bacon EJ, Richmond SJ, Wood DJ, Stirling P, Bevan BJ, Chalmers WS. (2017). Serological detection of phage infection in Chlamydia psittaci recovered from ducks. Vet. Rec. 119: 618–620. doi 10.1136/vr.119.25-26.618.

13. Barr JJ. (2017). A bacteriophages journey through the human body. Immunol. Rev. 279(1): 106–122.

14. Barr JJ, Auro R, Furlan M, Whiteson KL, Erb ML, Pogliano J, Stotland A, Wolkowicz R, Cutting AS, Doran KS, Salamon P, Youle M, Rohwer F. (2013). Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl. Acad. Sci. U.S.A. 110(26): 10771–10776.

15. Barr JJ, Auro R, Sam-Soon N, Kassegne S, Peters G, Bonilla N, Hatay M, Mourtada S, Bailey B, Youle M, Felts B, Baljon A, Nulton P, Salamon J, Rohwer F. (2015). Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters. PNAS. 112: 13675–13680.

16. Barreira DM, Ferreira MS, Fumian TM, Checon R, de Sadovsky AD, Leite JP, Miagostovich MP, Spano LC. (2010). Viral load and genotypes of noroviruses in symptomatic and asymptomatic children in southeastern Brazil. J. Clin. Virol. 47: 60–64. Epub 2009 Dec 8.

17. Barker J, Vipond IB, Bloomfield SF. (2004). Effects of cleaning and disinfection in reducing the spread of norovirus contamination via environmental surfaces. J. Hosp. Infect. 58: 42–49.

18. Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, Diamond MS, Miller VL, Virgin HW. (2007). Herpesvirus latency confers symbiotic protection from bacterial infection. Nature. 447: 326–329.

19. Basic M, Keubler LM, Buettner M, Achard M, Breves G, Schroder B, Smoczek A, Jorns A, Wedekind D, Zschemisch NH, Gunther C, Neumann D, Lienenklaus S, Weiss S, Hornef MW, Mahler M, Bleich A. (2014). Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm. Bowel Dis. 20: 431–443.

20. Bengmark S. (2012). Gut microbiota, immune development and function. Pharmacol Res. 7: 1023–1029. Epub 2012 Sep 16.

21. Bourdin G, Navarro A, Sarker SA, Pittet AC, Qadri F, Sultana S, Cravioto A, Talukder KA, Reuteler G, Brussow H. (2014). Coverage of diarrhoea-associated Escherichia coli isolates from different origins with two types of phage cocktails. Microb. Biotechnol. 7: 165–176.

22. Breitbart M, Bonnain C, Malki K, Sawaya NA. (2018). Phage puppet masters of the marine microbial realm. Nature microbiology. 3: 754–766.

23. Breitbart M, Hewson I, Felts B, Mahaffy JM, Nulton J, Salamon P, Rohwer F. (2003). Metagenomic analysis of an uncultured viral community from human feces. J. Bacteriol. 185: 6220–6223.

24. Breitbart M, Haynes M, Kelley S, Angly F, Edwards RA, Felts B, Mahaffy JM, Mueller J, Nulton J, Rayhawk S, Rodriguez-Brito B, Salamon P, Rohwer F. (2008). Viral diversity and dynamics in an infant gut. Res. Microbiol. 159: 367–373. Epub 2008 May 1.

25. Breitbart M, Rohwer F. (2004). Global distribution of nearly identical phage-encoded DNA sequences. FEMS Microbiol. Lett. 236: 249–256.

26. Breitbart M, Rohwer F. (2005). Here a virus, there a virus, everywhere the same virus? Trends Microbiol. 13: 278–284.

27. Breitbart M, Rohwer F. (2005). Method for discovering novel DNA viruses in blood using viral particle selection and shotgun sequencing. Biotechniques. 39: 729–736.

28. Brown-Jaque M, Muniesa M, Navarro F. (2016). Bacteriophages in clinical samples can interfere with microbiological diagnostic tools. Sci. Rep. 6.

29. Cadwell K. (2015). The virome in host health and disease. Immunity. 42(5): 805–813.

30. Carding SR, Davis N, Hoyles L. (2017). Review article: the human intestinal virome in health and disease. Aliment Pharmacol Ther. 46(9): 800–815. Epub 2017 Sep 4.

31. Castro-Mejia JL, Muhammed MK, Kot W, Neve H, Franz CM, Hansen LH, Vogensen FK, Nielsen DS. (2015). Optimizing protocols for extraction of bacteriophages prior to metagenomic analyses of phage communities in the human gut. Microbiome. 3: 64.

32. Chan BK, Abedon ST, Loc-Carrillo C. (2013). Phage cocktails and the future of phage therapy. Future Microbiol. 8: 769–783.

33. Chopra S, Harjai K, Chhibber S. (2016). Potential of combination therapy of endolysin MR-10 and minocycline in treating MRSA induced systemic and localized burn wound infections in mice. Int. J. Med. Microbiol. 306: 707–716. Epub 2016 Sep 1.

34. Cieplak T, Soffer N, Sulakvelidze A, Nielsen DS. (2018). A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota. Gut Microbes. 9(5): 391–399.

35. Colomer-Lluch M, Jofre J, Muniesa M. (2011). Antibiotic resistance genes in the bacteriophage DNA fraction of environmental samples. PLoS ONE. 6(3): e17549.

36. Colson P, Pagnier I, Yoosuf N, Fournous G, La Scola B, Raoult D. (2013). 'Marseilleviridae', a new family of giant viruses infecting amoebae. Arch. Virol. 158: 915–920. Epub 2012 Nov 29.

37. Costello EK, Stagaman K, Dethlefsen L, Bohannan BJ, Relman DA. (2012). The application of ecological theory toward an understanding of the human microbiome. Science. 336: 1255–1262. Epub 2012 Jun 6.

38. Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA et al. (2016). Alternatives to antibiotics – a pipeline portfolio review. Lancet. Infect. Dis. 16: 239–251. Epub 2016 Jan 13.

39. Dabrowska K, Miernikiewicz P, Piotrowicz A, Hodyra K, Owczarek B, Lecion D et al. (2014). Immunogenicity studies of proteins forming the T4 phage head surface. J. Virol. 88: 12551–12557. Epub 2014 Aug 20.

40. Dalmasso M, Hill C, Ross RP. (2014). Exploiting gut bacteriophages for human health. Trends Microbiol. 22: 399–405. Epub 2014 Mar 20.

41. Davies EV, Winstanley C, Fothergill JL, James CE. (2016). The role of temperate bacteriophages in bacterial infection. FEMS Microbiol. Lett. 363(5): fnw015.

42. Davies MR, Broadbent SE, Harris SR, Thomson NR, van der Woude MW. (2013). Horizontally acquired glycosyltransferase operons drive salmonellae lipopolysaccharide diversity. PLoS Genetics. 9(6): e1003568.

43. Delwart E. (2013). A roadmap to the human virome. PLoS Pathog. 9.; PMid:23457428 PMCid:PMC3573120. Epub 2013 Feb 14.

44. De Paepe M, Leclerc M, Tinsley CR, Petit M-A. (2014). Bacteriophages: an underestimated role in human and animal health? Front. Cell. Infect. Microbiol. 4: 39.

45. De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff N F, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR. (2013). Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 155: 1178–1187.

46. D'Herelle F. (1917). Sur un microbe invisible antagoniste des bacilles dysenteriques (An invisible microbe that is antagonistic to the dysentery bacillus). Comptes rendus Acad. Sciences. 165: 373–375.

47. Duerkop B, Clements C, Rollins D, Rodrigues J, Hooper L. (2012). A composite bacteriophage alters colonization by an intestinal commensal bacterium. Proceedings of the National Academy of Sciences. 109(43): 17621–17626. Epub 2012 Oct 8.

48. Duerkop BA, Hooper LV. (2013). Resident viruses and their interactions with the immune system. Nature immunology. 14: 654–659.

49. Dutilh BE, Cassman N, McNair K, Sanchez SE, Silva GGZ, Barr JJ, Speth DR, Seguritan V, Aziz RK, Felts B, Dinsdale EA, Mokili JL, Edwards RA. (2014). A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes. Nature Communications. 5: 4498–4512.

50. Dutilh BE, Reyes A, Hall RJ, Whiteson KL. (2017). Editorial: Virus Discovery by Metagenomics: The (Im)possibilities. Front Microbiol. 8: 1710.

51. Eckardt AJ, Baumgart DC. (2011). Viral gastroenteritis in adults. Recent Pat. Antiinfect. Drug Discov. 6(1): 54–63.; PMid:21210762.

52. Enault F, Briet A, Bouteille L, Roux S, Sullivan MB, Petit MA. (2017). Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. ISME J. 11: 237–247. Epub 2016 Jun 21.

53. Endersen L, O'Mahony J, Hill C, Ross RP, McAuliffe O, Coffey A. (2014). Phage therapy in the food industry. Annu Rev. Food Sci. Technol. 5: 327–349. Epub 2014 Jan 9.

54. Engels EA, Pfeiffer RM, Fraumeni JF, Kasiske BL, Israni AK, Snyder JJ, Wolfe RA, Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML, Goodman MT, Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams MA, Castenson D, Curry M, Parsons R, Fant G, Lin M. (2011). Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 306: 1891–1901.

55. Eriksson F, Culp WD, Massey R, Egevad L, Garland D, Persson MA, Pisa P. (2007). Tumor specific phage particles promote tumor regression in a mouse melanoma model. Cancer Immunol Immunother. 56(5): 677–687.

56. Eriksson F, Tsagozis P, Lundberg K, Parsa R, Mangsbo SM, Persson MA, Harris RA, Pisa P. (2009). Tumor-specific bacteriophages induce tumor destruction through activation of tumor-associated macrophages. J. Immunol. 182(5): 3105–3111.

57. Esparcia O, Montemayor M, Ginovart G, Pomar V, Soriano G, Pericas R et al. (2011). Diagnostic accuracy of a 16S ribosomal DNA gene-based molecular technique (RT-PCR, microarray, and sequencing) for bacterial meningitis, early-onset neonatal sepsis, and spontaneous bacterial peritonitis. Diagn. Microbiol. Infect. Dis. 69: 153–160.

58. Fasano A. (2011). Leaky Gut and Autoimmune Diseases. Clin. Rev. Allergy Immunol. 42: 71–78.

59. Fothergill JL, Mowat E, Walshaw MJ, Ledson MJ, James CE, Winstanley C. (2011). Effect of antibiotic treatment on bacteriophage production by a cystic fibrosis epidemic strain of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 55: 426–428. Epub 2010 Oct 25.

60. Fountizalis C, Patel S, Mahalingam D. (2017). Review: oncolytic virotherapy, updates and future directions. Oncotarget. 8(60): 102617–102639. doi 10.18632/oncotarget.18309. eCollection 2017 Nov 24.

61. Foxman EF, Iwasaki A. (2011). Genome-virome interactions: examining the role of common viral infections in complex disease. Nat. Rev. Microbiol. 9: 254–264.

62. Friis-Nielsen J, Kjartansdottir KR, Mollerup S, Asplund M, Mourier T, Jensen RH, Hansen TA, Rey-Iglesia A, Richter SR, Nielsen IB, Alquezar-Planas DE, Olsen PV, Vinner L, Fridholm H, Nielsen LP, Willerslev E, Sicheritz-Ponten T, Lund O, Hansen AJ, Izarzugaza JM, Brunak S. (2016). Identification of known and novel recurrent viral sequences in data from multiple patients and multiple cancers. Viruses. 8(2): 53.

63. Gabbay YB, Luz CR, Costa IV, Cavalcante-Pepino EL, Sousa MS, Oliveira KK, Wanzeller AL, Mascarenhas JD, Leite JP, Linhares AC. (2005). Prevalence and genetic diversity of astroviruses in children with and without diarrhea in Sao Luis, Maranhao, Brazil. Mem. Inst. Oswaldo Cruz. 100: 709–714.; PMid:16410955

64. Gabisoniya TG, Loladze MZ, Nadiradze MM, Chakhunashvili NK, Alibegashvili MG, Tamarashvili NG, Pushkina VA. (2016). Effects of bacteriophages on biofilm formation by strains of Pseudomonas aeruginosa. Appl. Biochem. Microbiol. 52: 293–297.

65. Gansauge MT, Meyer M. (2013). Single-stranded DNA library preparation for the sequencing of ancient or damaged DNA. Nat. Protoc. 8: 737–748. Epub 2013 Mar 14.

66. Gilbert C, Cordaux R. (2017). Viruses as vectors of horizontal transfer of genetic material in eukaryotes. Curr Opin Virol. 25: 16–22. Epub 2017 Jun 30.

67. Gorski A, Jonczyk-Matysiak E, Miedzybrodzki R, Weber-Dabrowska B, Lusiak-Szelachowska M, Baginska N, Borysowski J, Lobocka MB, Wegrzyn A, Wegrzyn G. (2018). Phage Therapy: Beyond Antibacterial Action. Front Med (Lausanne). 5: 146. doi 10.3389/fmed.2018.00146. eCollection 2018.

68. Gorski A, Miedzybrodzk R, Borysowski J, Dabrowska K, Wierzbicki P, Ohams M et al. (2012). Phage as a modulator of immune responses: practical implications for phage therapy. Adv. Virus Res. 83: 41–71.

69. Gorski A, Miedzybrodzki R, Weber-Dabrowska B, Fortuna W, Letkiewicz S, Rogoz P, Jonczyk-Matysiak E, Dabrowska K, Majewska J, Borysowski J. (2016). Phage therapy: combating infections with potential for evolving from merely a treatment for complications to targeting diseases. Front. Microbiol. 7: 1515.

70. Gorski A, Wazna E, Dabrowska BW, Dabrowska K, Switala-Jelen K, Miedzybrodzki R. (2006). Bacteriophage translocation. FEMS Immunol. Med. Microbiol. 46: 313–319. doi 10.1111/j.1574-695X.2006.00044.x.

71. Gorski A, Weber-Dabrowska B. (2005). The potential role of endogenous bacteriophages in controlling invading pathogens. Cell Mol. Life Sci. 62: 511–519.

72. Grandi N, Tramontano E. (2017). Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology. Viruses. 9(7): 162.; PMid:28653997 PMCid:PMC5537654

73. Guarino A, Wudy A, Basile F, Ruberto E, Buccigrossi V. (2012). Composition and roles of intestinal microbiota in children. J. Matern. Fetal. Neonatal. Med. 25(1): 63–66. Epub 2012 Mar 5.

74. Hamzeh-Mivehroud M, Mahmoudpour A, Rezazadeh H, Dastmalchi S. (2008). Non-specific translocation of peptide-displaying bacteriophage particles across the gastrointestinal barrier. Eur. J. Pharm. Biopharm. 70(2): 577–581. Epub 2008 Jun 17.

75. Hanahan D, Weinberg RA. (2011). Hallmarks of cancer: the next generation. Cell. 144(5): 646–674.

76. Handley SA, Thackray LB, Zhao G, Presti R, Miller AD, Droit L, Abbink P, Maxfield L.F, Kambal A, Duan E, Stanley K, Kramer J, Macri SC, Permar SR, Schmitz JE, Mansfield K, Brenchley JM, Veazey RS, Stappenbeck TS, Wang D, Barouch DH, Virgin HW. (2012). Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell. 151(2): 253–266.

77. Hannigan GD, Duhaime MB, Koutra D, Schloss PD. (2018). Biogeography and environmental conditions shape bacteriophage-bacteria networks across the human microbiome. PLoS Comput Biol. 14(4): e1006099.

78. Hannigan GD, Meisel JS, Tyldsley AS, Zheng Q, Hodkinson BP, SanMiguel AJ, Minot S, Bushman FD, Grice EA. (2015). The Human Skin Double-Stranded DNA Virome: Topographical and Temporal Diversity, Genetic Enrichment, and Dynamic Associations with the Host Microbiome. mBio. 6: e01578–15.

79. Hong Y, Thimmapuram J, Zhang J, Collings CK, Bhide K, Schmidt K, Ebner PD. (2016). The impact of orally administered phages on host immune response and surrounding microbial communities. Bacteriophage. 6(3): e1211066.

80. Horvath P, Barrangou R. (2010). CRISPR/Cas, the immune system of bacteria and archaea. Science. 327(5962): 167–170.

81. Hoyles L, McCartney AL, Neve H, Gibson GR, Sanderson JD, Heller KJ, van Sinderen D. (2014). Characterization of virus-like particles associated with the human faecal and caecal microbiota. Res. Microbiol. 165: 803–812. doi 10.1016/j.resmic.2014.10.006. Epub 2014 Oct 22.

82. Jagdale SS, Joshi RS. (2018). Enemies with benefits: mutualistic interactions of viruses with lower eukaryotes. Arch. Virol. 163(4): 821–830. Epub 2018 Jan 6.

83. Jover LF, Effler TC, Buchan A, Wilhelm SW, Weitz JS. (2014). The elemental composition of virus particles: implications for marine biogeochemical cycles. Nature Reviews Microbiology. 12: 519–528.

84. Kernbauer E, Ding Y, Cadwell K. (2014). An enteric virus can replace the beneficial function of commensal bacteria. Nature. 516: 94–98. Epub 2014 Nov 19.

85. Kim M, Lee H, Chang KO, Ko G. (2009). Molecular characterization of murine norovirus isolates from South Korea. Virus Res. 147: 1–6. Epub 2009 Sep 30.

86. Koskella B. (2014). Bacteria-phage interactions across time and space: merging local adaptation and time-shift experiments to understand phage evolution. Am. Nat. 184(1): 9–21. Epub 2014 Jul 8.

87. Koskella B, Brockhurst MA. (2014). Bacteria-phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiology Reviews. 38: 916–931.

88. Kowarsky M, Camunas-Soler J, Kertesz M, De Vlaminck I, Koh W, Pan W, Martin L, Neff NF, Okamoto J, Wong RJ, Kharbanda S, El-Sayed Y, Blumenfeld Y, Stevenson DK, Shaw GM, Wolfe ND, Quake SR. (2017). Numerous uncharacterized and highly divergent microbes, which colonize humans, are revealed by circulating cell-free DNA. Proc. Natl. Acad. Sci. USA. 114(36): 9623–9628.

89. Ksendzovsky A, Walbridge S, Saunders RC, Asthagiri AR, Heiss JD, Lonser RR. (2012). Convection-enhanced delivery of M13 bacterio-phage to the brain. J. Neurosurg. 117(2): 197–203. Epub 2012 May 18.

90. Lang AS, Zhaxybayeva O, Beatty JT. (2012). Gene transfer agents: phage-like elements of genetic exchange. Nat. Rev. Microbiol. 10: 472–482.

91. Lederberg J, McCray AT. (2001). 'Ome sweet' omics – A genealogical treasury of words. Scientist. 15(7): 8.

92. Lee YK, Mazmanian SK. (2010). Has the microbiota played a critical role in the evolution of the adaptive immune system. Science. 330(6012): 1768–1773.

93. Lepage P, Colombet J, Marteau P, Sime-Ngando T, Dore J, Leclerc M. (2008). Dysbiosis in inflammatory bowel disease: a role for bacteriophages? Gut. 57: 424–425.

94. Lim ES, Zhou Y, Zhao G et al. (2015). Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat. Med. 21: 1228–1234. Epub 2015 Sep 14.

95. Lin DM, Koskella B, Lin HC. (2017). Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther. 8(3): 162–173.; PMid:29186634.

96. Littman DR, Pamer EG. (2011). Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microbe. 10: 311–323. doi 10.4292/wjgpt.v8.i3.162.

97. Lusiak-Szelachowska M, Weber-Dabrowska B, Jonczyk-Matysiak E, Wojciechowska R, Gorski A. (2017). Bacteriophages in the gastrointestinal tract and their implications. Gut Pathog. 9: 44.

98. Ly M, Abeles SR, Boehm TK, Robles-Sikisaka R, Naidu M, Santiago-Rodriguez T et al. (2014). Altered Oral Viral Ecology in Association with Periodontal Disease. mBio. 5(3): e01133–14.

99. Ly M, Jones MB, Abeles SR et al. (2016). Transmission of viruses via our microbiomes. Microbiome. 4: 64.

100. Ma Y, You X, Mai G, Tokuyasu T, Liu C. (2018). A human gut phage catalog correlates the gut phageome with type 2 diabetes. Microbiome. 6: 24.

101. Malik DJ, Sokolov IJ, Vinner GK, Mancuso F, Cinquerrui S, Vladisavljevic GT, Clokie MRJ, Garton NJ, Stapley AGF, Kirpichnikova A. (2017). Formulation, stabilisation and encapsulation of bacteriophage for phage therapy. Adv. Colloid Interface Sci. 249: 100–133. Epub 2017 May 14.

102. Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ. (2016). Healthy human gut phageome. Proc. Natl. Acad. Sci. USA. 113: 10400–10405. Epub 2016 Aug 29.

103. Manrique P, Dills M, Young MJ. (2017). The human gut phage community and its implications for health and disease. Viruses. 9: 141. pii: E141. doi 10.3390/v9060141.

104. Marraffini LA, Sontheimer EJ. (2010). Self versus non-self discrimination during CRISPR RNA-directed immunity. Nature. 463: 568–571. Epub 2010 Jan 13.

105. Martinez-Castillo A, Muniesa M. (2014). Implications of free Shiga toxin-converting bacteriophages occurring outside bacteria for the evolution and the detection of Shiga toxin-producing Escherichia coli. Front. Cell. Infect. Microbiol. 4: 46. doi 10.3389/fcimb.2014.00046. eCollection 2014.

106. Mavrich TN, Hatfull GF. (2017). Bacteriophage evolution differs by host, lifestyle and genome. Nat. Microbiol. 2: 17112.

107. Matsuzaki S, Rashel M, Uchiyama J, Sakurai S, Ujihara T, Kuroda M, Imai S, Ikeuchi M, Tani T, Fujieda M et al. (2005). Bacteriophage therapy: A revitalized therapy against bacterial infectious diseases. J. Infect. Chemother. 11: 211–219.

108. Messing J. (2016). Phage M13 for the treatment of Alzheimer and Parkinson disease. Gene. 583: 85–89. Epub 2016 Feb 8.

109. Miernikiewicz P, Klopot A, Soluch R, Szkuta P, Keska W, Hodyra-Stefaniak K et al. (2016). T4 phage tail adhesion Gp12 counteracts LPS-induced inflammation in vivo. Front. Microbiol. 7: 1112.

110. Mills S, Shanahan F, Stanton C, Hill C, Coffey A, Ross RP. (2013). Movers and shakers: influence of bacteriophages in shaping the mammalian gut microbiota. Gut Microbes. 4(1): 4–16. Epub 2012 Sep 28.

111. Minagar A, Alexander J. (2003). Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. J. 9: 540–549.;

112. Minot S, Bryson A, Chehoud C, Wu GD, Lewis JD, Bushman FD. (2013). Rapid evolution of the human gut virome. Proc. Natl. Acad. Sci. USA. 110: 12450–12455. Epub 2013 Jul 8.

113. Minot S, Grunberg S, Wu GD, Lewis JD, Bushman FD. (2012). Hypervariable loci in the human gut virome. Current Issue. 109(10): 3962–3966.

114. Minot S, Sinha R, Chen J, Li H, Keilbaugh SA, Wu GD, Lewis JD, Bushman FD. (2011). The human gut virome: Inter-individual variation and dynamic response to diet. Genome Res. 21(10): 1616–1625. Epub 2011 Aug 31.

115. Mishra N, Pereira M, Rhodes RH, An P, Pipas JM, Jain K, Kapoor A, Briese T, Faust PL, Lipkin WI. (2014). Identification of a novel polyomavirus in a pancreatic transplant recipient with retinal blindness and vasculitic myopathy. J. Infect. Dis. 210: 1595–1599. Epub 2014 May 1.

116. Modi SR, Collins JJ, Relman DA. (2014). Antibiotics and the gut microbiota. J. Clin. Invest. 124(10): 4212–4218.

117. Modi SR, Lee HH, Spina CS, Collins JJ. (2013). Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature. 499: 219–222. Epub 2013 Jun 9.

118. Mokili JL, Rohwer F, Dutilh BE. (2012). Metagenomics and future perspectives in virus discovery. Curr. Opin. Virol. 2: 63–77. Epub 2012 Jan 20.

119. Monaco CL, Gootenberg DB, Zhao G, Handley SA, Ghebremichael MS, Lim ES et al. (2016). Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. Cell Host and Microbe. 19: 311–322.

120. Monaco CL, Kwon DS. (2017). «Next-generation Sequencing of the DNA Virome from Fecal Samples». Bio-protocol. 7(5). pii: e2159.

121. Montgomery ND, Parker JS, Eberhard DA, Patel NM, Weck KE, Sharpless NE, Hu Z, Hayes DN, Gulley ML. (2016). Identification of human papillomavirus infection in cancer tissue by targeted next-generation sequencing. Appl. Immunohistochem Mol. Morphol. 24: 490–495.

122. Moon BY, Park JY, Hwang SY, Robinson DA, Thomas JC, Fitzgerald JR et al. (2015). Phage-mediated horizontal transfer of a Staphylococcus aureus virulence-associated genomic island. Scientific Reports. 5: 9784.

123. Nakamura S, Yang CS, Sakon N et al. (2009). Direct metagenomic detection of viral pathogens in nasal and fecal specimens using an unbiased high-throughput sequencing approach. PLoS ONE. 4: e4219. Epub 2009 Jan 19.

124. Nannapaneni R, Soni KA. USA: John Wiley & Sons, Ltd; (2015). Use of Bacteriophages to Remove Biofilms of Listeria monocytogenes and other Foodborne Bacterial Pathogens in the Food Environment. Biofilms in the Food Environment, Second Edition: 131–144.

125. Navarro F, Muniesa M. (2017). Phages in the Human Body. Front Microbiol. 8: 566.

126. Nguyen S, Baker K, Padman B, Patwa R, Dunstan R, Weston T, Schlosser K, Bailey B, Lithgow T, Lazarou M et al. (2017). Bacteriophage Transcytosis Provides a Mechanism to Cross Epithelial Cell Layers. mBio. 8: e01874–17.

127. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC et al. (2015). Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 160: 447–460. Epub 2015 Jan 22.

128. Norman JM, Handley SA, Virgin HW. (2014). Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology. 146: 1459–1469. Epub 2014 Feb 5.

129. Ogilvie LA, Bowler LD, Caplin J et al. (2013). Genome signature-based dissection of human gut metagenomes to extract subliminal viral sequences. Nat. Commun. 4: 2420.

130. Ogilvie LA, Caplin J, Dedi C et al. (2012). Comparative (meta)genomic analysis and ecological profiling of human gut-specific bacteriophage ϕB124-14. PLoS ONE. 7: e35053. Epub 2012 Apr 25.

131. Oliveira H, Vilas Boas D, Mesnage S, Kluskens LD, Lavigne R, Sillankorva S, Secundo F, Azeredo J. (2016). Structural and Enzymatic Characterization of ABgp46, a Novel Phage Endolysin with Broad Anti-Gram-Negative Bacterial Activity. Front Microbiol. 7: 208. doi 10.3389/fmicb.2016.00208. eCollection 2016.

132. Oliveira M, Vinas I, Colas P, Anguera M, Usall J, Abadias M. (2014). Effectiveness of a bacteriophage in reducing Listeria monocytogenes on fresh-cut fruits and fruit juices. Food Microbiol. 38: 137–142. Epub 2013 Sep 11.

133. Ott SJ, Waetzig GH, Rehman A et al. (2017). Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology. 152: 799–811. Epub 2016 Nov 17.

134. Parker MT. (2016). An ecological framework of the human virome provides classification of current knowledge and identifies areas of forthcoming discovery. Yale J. Biol. Med. 89: 339–351. eCollection 2016 Sep.

135. Penades JR, Chen J, Quiles-Puchalt N, Carpena N, Novick RP. (2015). Bacteriophage-mediated spread of bacterial virulence genes. Curr. Opin. Microbiol. 23: 171–178. Epub 2014 Dec 19.

136. Penner JC, Ferreira JA, Secor PR, Sweere JM, Birukova M, Joubert LM et al. (2016). Pf4 bacteriophage produced by Pseudomonas aeruginosa inhibits Aspergillus fumigates metabolism via iron sequestration. Microbiology. 162(9): 1583–1594.

137. Perez-Brocal V, Garcia-Lopez R, Nos P, Beltran B, Moret I, Moya A. (2015). Metagenomic analysis of Crohn's disease patients identifies changes in the virome and microbiome related to disease status and therapy, and detects potential interactions and biomarkers. Inflamm. Bowel Dis. 21: 2515–2532. doi 10.1097/MIB.0000000000000549.

138. Pincus NB, Reckhow JD, Saleem D, Jammeh ML, Datta SK, Myles IA. (2015). Strain Specific Phage Treatment for Staphylococcus aureus Infection Is Influenced by Host Immunity and Site of Infection. PLoS One. 10: e0124280. doi 10.1371/journal.pone.0124280. eCollection 2015.

139. Popgeorgiev N, Boyer M, Fancello L, Monteil S, Robert C, Rivet R, Nappez C, Azza S, Chiaroni J, Raoult D, Desnues C. (2013). Marseillevirus-like virus recovered from blood donated by asymptomatic humans. J. Infect. Dis. 208(7): 1042–1050. Epub 2013 Jul 2.

140. Popgeorgiev N, Temmam S, Raoult D et al. (2013). Describing the Silent Human Virome with an Emphasis on Giant Viruses. Intervirology. 56: 395–412. Epub 2013 Oct 17.

141. Pride DT, Salzman J, Haynes M, Rohwer F, Davis-Long C, White RA, Loomer P, Armitage GC, Relman DA. (2012). Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome. ISME J. 6: 915–926. Epub 2011 Dec 8.

142. Przybylski M, Borysowski J, Jkaubowska-Zahorska R, Weber-Dabrowska B, Gorski A. (2015). T4 bacteriophage-mediated inhibition of adsorption and replication of human adenowirus in vitro. Future Microbiol. 10: 453–460.

143. Rakhuba DV, Kolomiets EI, Dey ES, Novik GI. (2010). Bacteriophage receptors, mechanisms of phage adsorption and penetration into host cell. Pol. J. Microbiol. 59: 145–155. doi 10.1016/j.micres.2015.

144. Reese TA, Wakeman BS, Choi HS, Hufford MM, Huang X, Zhang SC, Buck MD, Jezewski A, Kambal A, Liu CY, Goel G, Murray PJ, Xavier RJ, Kaplan MH, Renne R, Speck SH, Artyomov MN, Pearce EJ, Virgin HW. (2014). Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter. Science. 345(6196): 573–577.

145. Reyes A, Blanton LV, Cao S et al. (2015). Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc. Natl. Acad. Sci. USA. 112: 11941–11946.

146. Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, Gordon JI. (2010). Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 466: 334–338.

147. Reyes A, Wu M, McNulty NP, Rohwer FL, Gordon JI. (2013). Gnotobiotic mouse model of phage-bacterial host dynamics in the human gut. Proc. Natl. Acad. Sci. USA. 110: 20236–20241.

148. Roossinck MJ. (2015). Move over bacteria! Viruses make their mark as mutualistic microbial symbionts. J. Virol. 89(13): 6532–6535.

149. Roossinck MJ. (2011). The good viruses: viral mutualistic symbioses. Nat. Rev. Microbiol. 9: 99–108. Epub 2011 Jan 4.

150. Roux S, Krupovic M, Poulet A, Debroas D, Enault F. (2012). Evolution and diversity of the Microviridae viral family through a collection of 81 new complete genomes assembled from virome reads. PLoS ONE. 7: e40418.

151. Roux S, Solonenko NE, Dang VT et al. (2016). Towards quantitative viromics for both double-stranded and single-stranded DNA viruses. Peer J. 4: e2777. doi 10.7717/peerj.2777. eCollection 2016.

152. Samson A, Scott KJ, Taggart D, West EJ, Wilson E et al. (2018). Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Science Translational Medicine. 10(422). pii: eaam7577.

153. Santiago-Rodriguez TM, Ly M, Bonilla N, Pride DT. (2015). The human urine virome in association with urinary tract infections. Frontiers in Microbiology. 6: 14.

154. Santiago-Rodriguez T, Naidu M, Abeles S, Boehm T, Ly M, Pride D. (2015). Transcriptome analysis of bacteriophage communities in periodontal health and disease. BMC Genom. 16: 549.

155. Scheperjans F. (2016). Gut microbiota, 1013 new pieces in the Parkinson's disease puzzle. Curr. Opin. Neurol. 29: 773–780.

156. Selva L, Viana D, Regev-Yochay G, Trzcinski K, Corpa JM, Lasa I et al. (2009). Killing niche competitors by remote-control bacteriophage induction. Proc. Natl. Acad. Sci. U.S.A. 106: 1234–1238. Epub 2009 Jan 13.

157. Shapiro L, Harmon W, Strom T, Bunn H. (2004). In utero detection of T7 phage after systemic administration to pregnant mice. Biotechniques: 37: 81–83.

158. Shen W, Patnaik MM, Ruiz A, Russell SJ, Peng KW. (2016). Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia. Blood. 127(11): 1449–1458. Epub 2015 Dec 28.

159. Scanlan PD, Buckling A. (2012). Co-evolution with lytic phage selects for the mucoid phenotype of Pseudomonas fluorescens SBW25. ISME J. 6: 1148–1158. Epub 2011 Dec 22.

160. Smits L, Osterhaus ADME. (2010). Human picobirnaviruses identified by molecular screening of diarrhea samples. J. of Clin. Microbiology. 48(5): 1787–1794. Epub 2010 Mar 24.

161. Sridhar S, To KK, Chan JF, Lau SK, Woo PC, Yuen KY. (20150. A systematic approach to novel virus discovery in emerging infectious disease outbreaks. J. Mol. Diagn. 17: 230–241. doi 10.1016/j.jmoldx.2014.12.002. Epub 2015 Mar 4.

162. Stern A, Mick E, Tirosh I, Sagy O, Sorek R. (2012). CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome. Genome Res. 22: 1985–1994. Epub 2012 Jun 25.

163. Sullivan MB, Weitz JS, Wilhelm S. (2017). Viral ecology comes of age. Environ Microbiol Rep. 9: 33–35.

164. Sun L, Nava GM, Stappenbeck TS. (2011). Host genetic susceptibility, dysbiosis, and viral triggers in inflammatory bowel disease. Curr. Opin. Gastroenterol. 27: 321–327.

165. Suttle CA. (2005). Viruses in the sea. Nature. 437: 356–361.

166. Tan SK, Relman DA, Pinsky BA. (2017). The Human Virome: Implications for Clinical Practice in Transplantation Medicine. J. Clin. Microbiol. 55(10): 2884–2893. Epub 2017 Jul 19.

167. Tetz G, Brown S, Hao Y, Tetz V. (2018). Parkinsons disease and bacteriophages as its overlooked contributors. bioRxiv.

168. Tetz G, Ruggles K, Zhou H, Heguy A, Tsirigos A, Tetz V. (2017). Bacteriophages as potential new mammalian pathogens. Sci. Rep. 7: 7043.

169. Tetz G, Tetz V. (2018). Bacteriophages as New Human Viral Pathogens. Microorganisms. 6(2): 54.

170. Tetz G, Tetz V. (2016). Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gut Pathog. 8: 33.

171. Tetz G, Tetz V. (2017). Prion-Like Domains in Phagobiota. Front. Microbiol. 8: 2239.

172. Torres-Barcelo C, Hochberg ME. (2016). Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol. 24: 249–256. Epub 2016 Jan 17.

173. Tremaroli V, Backhed F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature. 489: 242–249.

174. Ventura M, Sozzi T, Turroni F, Matteuzzi D, van Sinderen D. (2011, Aug). The impact of bacteriophages on probiotic bacteria and gut microbiota diversity. Genes Nutr. 6; 3: 205–207.

175. Verbeken G, Huys I, DeVos D, De Coninck A, Roseeuw D, Kets E et al. (2016). Access to bacteriophage therapy: discouraging experiences from the human cell and tissue legal framework. FEMS Microbiol. 363(4). pii: fnv241. Epub 2015 Dec 16.

176. Virgin HW. (2014). The virome in mammalian physiology and disease. Cell. 157: 142–150.

177. Virgin HW, Wherry EJ, Ahmed R. (2009). Redefining chronic viral infection. Cell. 138: 30–50.

178. Viruses Flourish in Guts of Healthy Babies. (2015). Materials provided by Washington University School of Medicine. doi 10.1038/nm.3950.

179. Wang W, Jovel J, Halloran B et al. (2015). Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm. Bowel Dis. 21: 1419–1427. doi 10.1097/MIB.0000000000000344.

180. Weber-Dabrowska B, Mulczyk M, Gorski A. (2003). Bacteriophages as an efficient therapy for antibiotic-resistant septicemia in man. Transplant. Proc. 35: 1385–1386. PMID:12826166.

181. Weinbauer MG. (2004). Ecology of prokaryotic viruses. FEMS Microbiol. Rev. 28: 127–181.

182. White DW, Beard RS, Barton ES. (2012). Immune modulation during latent herpesvirus infection. Immunol. Reviews. 245(1): 189–208.

183. White DW, Keppel CR, Schneider SE, Reese TA, Coder J, Payton JE, Ley TJ, Virgin HW, Fehniger TA. (2010). Latent herpesvirus infection arms NK cells. Blood. 115: 4377–4383. Epub 2010 Feb 4.

184. Willner D, Furlan M, Haynes M et al. (2009). Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS ONE. 4: e7370.

185. Woolhouse M, Scott F, Hudson Z, Howey R, Chase-Topping M. (2012). Human viruses: discovery and emergence. Philos Trans. R. Soc. Lond. B. Biol. Sci. 367: 2864–2871.

186. Wylie KM, Weinstock GM, Storch GA. (2013). Virome genomics: a tool for defining the human virome. Curr. Opin. Microbiol. 16: 479–484. Epub 2013 May 23.

187. Zhang T, Breitbart M, Lee WH et al. (2006). RNA viral community in human feces: prevalence of plant pathogenic viruses. PLoS Biol. 4: e3.

188. Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, Acheson DW. (2000). Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J. Infect. Dis. 181: 664–670.

189. Zhang XX, Zhang T, Fang HH. (2009). Antibiotic resistance genes in water environment. Appl. Microbiol. Biotechnol. 82: 397–414.; Epub 2009 Jan 8.

190. Zhao G, Vatanen T, Droit L, Park A, Kostic AD, Poon TW, Vlamakis H, Siljander H, Harkonen T, Hamolainen AM, Peet A, Tillmann V, Ilonen J, Wang D, Knip M, Xavier RJ, Virgin HW. (2017). Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. PNAS. 114(30): 6166–6175. Epub 2017 Jul 10.

191. Zhong X, Guidoni B, Jacas L, Jacquet S. (2015). Structure and diversity of ssDNA Microviridae viruses in two peri-alpine lakes (Annecy and Bourget, France). Res. Microbiol. 166: 644–654. Epub 2015 Jul 27.

192. Zuo T, Wong SH, Lam K et al. (2017). Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut. 67(4): 634–643.

193. Yang JY, Kim MS, Kim E et al. (2016). Enteric viruses ameliorate gut inflammation via Toll-like receptor 3 and Toll-like receptor 7-mediated interferon-β production. Immunity. 44: 889–900. Epub 2016 Apr 12.

194. Young R, Gill JJ. (2015). Phage therapy redux – what is to be done? Science. 350: 1163–1164.

Article received: Nov 03, 2018. Accepted for publication: Feb 08, 2019.