Published June 12, 2024 | Version v1
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Screening for a stable region in the T7 phage genome and repurposing Riboflavin as an anti-phage molecule

  • 1. ROR icon Istanbul University

Description

Over the past century, the emergence of antibiotic-resistant bacterial strains has heightened interest in bacteriophages. Advances in genomic engineering techniques have expanded the potential applications of phages across various fields. However, the long-term effects of phage therapy on the human body remain poorly understood. As a result of this study, a target constant region that is responsible for coding of the overcome classical restriction (Ocr) protein on T7 phage that provides protection from restriction enzymes was detected. A molecule called Riboflavin that interacts with this region could be used in the clearance of T7 phages. In addition, another docking study revealed that Ocr has an antitranscriptive effect on the Human Early B-cell Factor 1 (EBF1) DNA-binding domain, which affects the cellular processes. Confirmation of these findings by further clinical and in vitro studies will provide new insights into phage-human cell interactions and new phage-clearing treatments.  

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Funding

Scientific Research Projects Coordination Unit BYP-2019-34727
Istanbul University

References

  • 1 Rohwer F, Segall AM (2015) In retrospect: a century of phage lessons. Nature 528:46-48. https://doi.org/10.1038/528046a
  • 2 Clokie MR, Millard AD, Letarov AV, Heaphy S (2011) Phages in nature. Bacteriophage 1:31-45. https://doi.org/10.4161/bact.1.1.14942
  • 3 Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ (2016) Healthy human gut phageome. Proc Natl Acad Sci U S A 113:10400-10405. https://doi.org/10.1073/pnas.1601060113
  • 4 De Smet J, Hendrix H, Blasdel BG, Danis-Wlodarczyk K, Lavigne R (2017) Pseudomonas predators: understanding and exploiting phage-host interactions. Nat Rev Microbiol 15:517-530. https://doi.org/10.1038/nrmicro.2017.61
  • 5 Koskella B, Brockhurst MA (2014) Bacteria–phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiol Rev 38:916-931. https://doi.org/10.1111/1574-6976.12072
  • 6 Podlacha M, Grabowski Ł, Kosznik-Kawśnicka K, Zdrojewska K, Stasiłojć M, Węgrzyn G, Węgrzyn A (2021) Interactions of bacteriophages with animal and human organisms-safety issues in the light of phage therapy. Int J Mol Sci 22:8937. https://doi.org/10.3390/ijms22168937
  • 7 Gaidelyte A, Vaara M, Bamford DH (2007) Bacteria, phages and septicemia. PLoS One 2:e1145. https://doi.org/10.1371/journal.pone.0001145
  • 8 Fancello L, Monteil S, Popgeorgiev N, Rivet R, Gouriet F, Fournier PE, Raoult D, Desnues C (2014) Viral communities associated with human pericardial fluids in idiopathic pericarditis. PLoS One 9:e93367. https://doi.org/10.1371/journal.pone.0093367
  • 9 Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y, Bloom K, Delwart E, Nelson KE, Venter JC, Telenti A (2017) The blood DNA virome in 8,000 humans. PLoS Pathog 13:e1006292. https://doi.org/10.1371/journal.ppat.1006292
  • 10 Mie˛dzybrodzki R, Kłak M, Jon´czyk-Matysiak E, Bubak B, Wójcik A, Kaszowska M, Weber-Da˛browska B, Łobocka M, Górski A (2017) Means to facilitate the overcoming of gastric juice barrier by a therapeutic staphylococcal bacteriophage A5/80. Front Microbiol 8:467. https://doi.org/10.3389/fmicb.2017.00467
  • 11 Keller R, Engley FB Jr. (1958) Fate of bacteriophage particles introduced into mice by various routes. Proc Soc Exp Biol Med 98:577-580. https://doi.org/10.3181/00379727-98-24112
  • 12 Bogovazova GG, Voroshilova NN, Bondarenko VM (1991) Effektivnost' bakteriofaga Klebsiella pneumoniae pri terapii éksperimental'noĭ klebsielleznoĭ infektsii [The efficacy of Klebsiella pneumoniae bacteriophage in the therapy of experimental Klebsiella infection]. Zh Mikrobiol Epidemiol Immunobiol Apr(4):5-8. Russian.
  • 13 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. https://doi.org/10.1038/nature09199
  • 14 Minot S, Bryson A, Chehoud C, Wu GD, Lewis JD, Bushman FD (2013) Rapid evolution of the human gut virome. Proc Natl Acad Sci U S A 110:12450-12455. https://doi.org/10.1073/pnas.1300833110
  • 15 Handley SA, Thackray LB, Zhao G, Presti R, Miller AD, Droit L, Abbink P, Maxfield LF, 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 151:253-266. https://doi.org/10.1016/j.cell.2012.09.024
  • 16 Karimi M, Mirshekari H, Moosavi Basri SM, Bahrami S, Moghoofei M, Hamblin MR (2016) Bacteriophages and phage-inspired nanocarriers for targeted delivery of therapeutic cargos. Adv Drug Deliv Rev 106:45-62. https://doi.org/10.1016/j.addr.2016.03.003
  • 17 Tetz GV, Ruggles KV, Zhou H, Heguy A, Tsirigos A, Tetz V (2017) Bacteriophages as potential new mammalian pathogens. Sci Rep 7:7043. https://doi.org/10.1038/s41598-017-07278-6
  • 18 Tetz G, Brown SM, Hao Y, Tetz V (2018) Parkinson's disease and bacteriophages as its overlooked contributors. Sci Rep 8:10812. https://doi.org/10.1038/s41598-018-29173-4. Erratum in: Sci Rep. (2020) 10:12078.
  • 19 Tetz G, Tetz V 2018 Bacteriophages as New Human Viral Pathogens. Microorganisms. 6:54. https://doi.org/10.3390/microorganisms6020054
  • 20 Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, Kaber G, Manasherob R, Suh GA, Cao X, de Vries CR, Lam DN, Marshall PL, Birukova M, Katznelson E, Lazzareschi DV, Balaji S, Keswani SG, Hawn TR, Secor PR, Bollyky PL (2019) Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363:eaat9691. https://doi.org/10.1126/science.aat9691
  • 21 Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T (2017) Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother 61(10):e00954-17. https://doi.org/10.1128/aac.00954-17 Erratum in: Antimicrob Agents Chemother (2018) 62(12):e02221-18 https://doi.org/10.1128/aac.02221-18
  • 22 Jennes S, Merabishvili M, Soentjens P, Pang KW, Rose T, Keersebilck E, Soete O, François PM, Teodorescu S, Verween G, Verbeken G, De Vos D, Pirnay JP (2017) Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury-a case report. Crit Care 21:129. https://doi.org/10.1186/s13054-017-1709-y
  • 23 Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, Bourdin G, McCallin S, Ngom-Bru C, Neville T, Akter M, Huq S, Qadri F, Talukdar K, Kassam M, Delley M, Loiseau C, Deng Y, El Aidy S, Berger B, Brüssow H (2016) Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: A randomized trial in children from Bangladesh. EBioMedicine 4:124-137. https://doi.org/10.1016/j.ebiom.2015.12.023
  • 24 Jault P, Leclerc T, Jennes S, Pirnay JP, Que YA, Resch G, Rousseau AF, Ravat F, Carsin H, Le Floch R, Schaal JV, Soler C, Fevre C, Arnaud I, Bretaudeau L, Gabard J (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis 19:35-45. https://doi.org/10.1016/s1473-3099(18)30482-1
  • 25 Leitner L, Ujmajuridze A, Chanishvili N, Goderdzishvili M, Chkonia I, Rigvava S, Chkhotua A, Changashvili G, McCallin S, Schneider MP, Liechti MD, Mehnert U, Bachmann LM, Sybesma W, Kessler TM (2021) Intravesical bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomised, placebo-controlled, double-blind clinical trial. Lancet Infect Dis 21:427-436. https://doi.org/10.1016/s1473-3099(20)30330-3
  • 26 Bumunang EW, Zaheer R, Niu D, Narvaez-Bravo C, Alexander T, McAllister TA, Stanford K (2023) Bacteriophages for the targeted control of foodborne pathogens. Foods 12:2734. https://doi.org/10.3390/foods12142734
  • 27 Jones JB, Vallad GE, Iriarte FB, Obradović A, Wernsing MH, Jackson LE, Balogh B, Hong JC, Momol MT (2012) Considerations for using bacteriophages for plant disease control. Bacteriophage 2:208-214. https://doi.org/10.4161/bact.23857
  • 28 Villalpando-Aguilar JL, Matos-Pech G, López-Rosas I, Castelán-Sánchez HG, Alatorre-Cobos F (2022) Phage therapy for crops: Concepts, experimental and bioinformatics approaches to direct its application. Int J Mol Sci 24:325. https://doi.org/10.3390/ijms24010325
  • 29 Demerec M, Fano U (1945) Bacteriophage-resistant mutants in Escherichia coli. Genetics 30:119-136. https://doi.org/10.1093/genetics/30.2.119
  • 30 Cerritelli ME, Cheng N, Rosenberg AH, McPherson CE, Booy FP, Steven AC (1997) Encapsidated conformation of bacteriophage T7 DNA. Cell 91:271-280. https://doi.org/10.1016/s0092-8674(00)80409-2
  • 31 Yu T, Sun Z, Cao X, Pang Q, Deng H (2022) Recent trends in T7 phage application in diagnosis and treatment of various diseases. Int Immunopharmacol 110:109071. https://doi.org/10.1016/j.intimp.2022.109071
  • 32 Burland TG (2000) DNASTAR's Lasergene sequence analysis software. Methods Mol Biol 132:71-91. https://doi.org/10.1385/1-59259-192-2:71
  • 33 Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A (2003) ExPASy: the proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 31:3784-3788. https://doi.org/10.1093/nar/gkg563
  • 34 Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y (2015) The I-TASSER Suite: Protein structure and function prediction. Nat Methods 12:7-8. https://doi.org/10.1038/nmeth.3213
  • 35 Schüttelkopf AW, van Aalten DMF (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60:1355-1363. https://doi.org/10.1107/s0907444904011679
  • 36 Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455-461. https://doi.org/10.1002/jcc.21334
  • 37 Grosdidier A, Zoete V, Michielin O (2011) SwissDock, protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res 39 (suppl_2):W270-W277. https://doi.org/10.1093/nar/gkr366
  • 38 Walkinshaw MD, Taylor P, Sturrock SS, Atanasiu C, Berge T, Henderson R.M, Edwardson JM, Dryden DTF (2002) Structure of Ocr from Bacteriophage T7, a protein that mimics B-form DNA. Molecular Cell 9:187-194. https://doi.org/10.1016/S1097-2765(02)00435-5
  • 39 Siponen MI, Wisniewska M, Lehtiö L, Johansson I, Svensson L, Raszewski G, Nilsson L, Sigvardsson M, Berglund H (2010) Structural determination of functional domains in early B-cell factor (EBF) family of transcription factors reveals similarities to Rel DNA-binding proteins and a novel dimerization motif. J Biol Chem 285:25875-9. https://10.1074/jbc.C110.150482
  • 40 van Zundert GCP, Rodrigues JPGLM, Trellet M, Schmitz C, Kastritis PL, Karaca E, Melquiond ASJ, van Dijk M, de Vries SJ, Bonvin AMJJ (2016) The HADDOCK2.2 web server: User-friendly integrative modeling of biomolecular complexes. J Mol Biol 428:720-725. https://doi.org/10.1016/j.jmb.2015.09.014
  • 41 Schrödinger L, DeLano W (2020) The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC. http://www.pymol.org/pymol Accessed 7 July 2023.
  • 42 Baysal Ö, Abdul Ghafoor N, Silme RS, Ignatov AN, Kniazeva V (2021a) Molecular dynamics analysis of N-acetyl-D-glucosamine against specific SARS-CoV-2's pathogenicity factors. PloS One 16:e0252571. https://doi.org/10.1371/journal.pone.0252571
  • 43 Baysal Ö, Silme RS, Karaaslan İÇ, Ignatov AN (2021b) Genetic uniformity of a specific region in SARS-CoV-2 genome and repurposing of N-acetyl-d-glucosamine. Fresenius Environ Bull 30:2848-2857. https://doi.org/10.5281/zenodo.4621319
  • 44 Baysal Ö, Silme RS (2021) Utilization from computational methods and omics data for antiviral drug discovery to control of SARS-CoV-2. In: Kumar V (ed) Origin and impact of COVID-19 pandemic originating from SARS-CoV-2 infection across the globe. IntechOpen Limited, London, pp 1-15. https://doi.org/10.5772/intechopen.98319
  • 45 Abdul Ghafoor N, Kırboğa KK, Baysal Ö, Süzek BE, Silme RS (2023) Data mining and molecular dynamics analysis to detect HIV-1 reverse transcriptase RNase H activity inhibitor. Mol Divers https://doi.org/10.1007/s11030-023-10707-6
  • 46 Kruger DH, Schroeder C, Hansen S, Rosenthal HA (1977) Active protection by bacteriophages T3 and T7 against E. coli B- and K-specific restriction of their DNA. Mol Gen Genet 153:99-106. https://doi.org/10.1007/bf01036001
  • 47 Bandyopadhyay PK, Studier FW, Hamilton DL, Yuan R (1985) Inhibition of the type I restriction-modification enzymes EcoB and EcoK by the gene 0.3 protein of bacteriophage T7. J Mol Biol 182:567-578. https://doi.org/10.1016/0022-2836(85)90242-6
  • 48 Kruger DH, Schroeder C, Reuter M, Bogdarina IG, Buryanov YI, Bickle TA (1985) DNA methylation of bacterial viruses T3 and T7 by different DNA methylases in Escherichia coli K12 cells. Eur J Biochem 150:323-330. https://doi.org/10.1111/j.1432-1033.1985.tb09024.x
  • 49 Blackstock JJ, Egelhaaf SU, Atanasiu C, Dryden DTF, Poon WCK (2001) Shape of Ocr, the gene 0.3 protein of bacteriophage T7: modeling based on light scattering experiments. Biochemistry 40:9944-9949. https://doi.org/10.1021/bi010587+
  • 50 Atanasiu C, Byron O, McMiken H, Sturrock SS, Dryden DTF (2001) Characterisation of the structure of ocr, the gene 0.3 protein of bacteriophage T7. Nucleic Acids Res 29:3059-3068. https://doi.org/10.1093/nar/29.14.3059
  • 51 Sturrock SS, Dryden DTF, Atanasiu C, Dornan J, Bruce S, Cronshaw A, Taylor P, Walkinshaw MD (2001) Crystallisation and preliminary X-ray analysis of ocr, the product of gene 0.3 of bacteriophage T7. Acta Crystallogr D Biol Crystallogr 57:1652-1654. https://doi.org/10.1107/s0907444901011623
  • 52 Eskin B, Lautenberger JA, Linn S (1973) Host-controlled modification and restriction of bacteriophage T7 by Escherichia coli B. J Virol 11:1020-1023. https://doi.org/10.1128/jvi.11.6.1020-1023.1973
  • 53 Studier FW (1975) Gene 0.3 of bacteriophage T7 acts to overcome the DNA restriction system of the host. J Mol Biol 94:283-295. https://doi.org/10.1016/0022-2836(75)90083-2
  • 54 Zavilgelsky GB (2000) Antirestriction. Mol Biol (Mosk) 34:854-862.
  • 55 Dunn JJ, Elzinga M, Mark K-K, Studier FW (1981) Amino acid sequence of the gene 0.3 protein of bacteriophage T7 and nucleotide sequence of its mRNA. J Biol Chem 256:2579-2585.
  • 56 Thakur K, Tomar SK, Singh AK, Mandal S, Arora S (2017) Riboflavin and health: A review of recent human research. Crit Rev Food Sci Nutr 57:3650-3660. https://doi.org/10.1080/10408398.2016.1145104
  • 57 Suwannasom N, Kao I, Pruß A, Georgieva R, Bäumler H (2020) Riboflavin: the health benefits of a forgotten natural vitamin. Int J Mol Sci 21:950. https://doi.org/10.3390/ijms21030950
  • 58 Lei J, Xin C, Xiao W, Chen W, Song Z (2021) The promise of endogenous and exogenous riboflavin in anti-infection. Virulence 12:2314-2326. https://doi.org/10.1080/21505594.2021.1963909
  • 59 Farah N, Chin VK, Chong PP, Lim WF, Lim CW, Basir R, Chang SK, Lee TY (2022) Riboflavin as a promising antimicrobial agent? A multi-perspective review. Curr Res Microb Sci 3:100111. https://doi.org/10.1016/j.crmicr.2022.100111
  • 60 Rivlin RS (1970) Riboflavin metabolism. N Engl J Med 283:463-472. https://doi.org/10.1056/nejm197008272830906
  • 61 Heelis PF (1982) The photophysical and photochemical properties of flavins (isoalloxazines). Chem Soc Rev 11:15-39. https://doi.org/10.1039/CS9821100015
  • 62 Smith EC, DE Metzler (1963) The photochemical degradation of riboflavin. J Am Chem Soc 85:3285-3288. https://doi.org/10.1021/ja00903a051
  • 63 Zempleni J (1995) Determination of riboflavin and flavocoenzymes in human blood plasma by high-performance liquid chromatography. Ann Nutr Metab 39:224-226. https://doi.org/10.1159/000177866
  • 64 Zempleni J, Galloway JR, McCormick DB (1996) The identification and kinetics of 7 alpha-hydroxyriboflavin (7-hydroxymethylriboflavin) in blood plasma from humans following oral administration of riboflavin supplements. Int J Vitam Nutr Res 66:151-157.
  • 65 Kuratomi K, Kobayashi Y (1977) Studies on the interactions between DNA and flavins. Biochim Biophys Acta 476:207-217. https://doi.org/10.1016/0005-2787(77)90004-1
  • 66 Speck WT, Rosenkranz S, Rosenkranz HS (1976) Further observations on the photooxidation of DNA in the presence of Riboflavin. Biochim Biophys Acta 435:39-44. https://doi.org/10.1016/0005-2787(76)90189-1
  • 67 Ruane PH, Edrich R, Gampp D, Keil SD, Leonard RL, Goodrich RP (2004) Photochemical inactivation of selected viruses and bacteria in platelet concentrates using riboflavin and light. Transfusion 44:877-885. https://doi.org/10.1111/j.1537-2995.2004.03355.x
  • 68 Tsugita A, Okada Y, Uehara K (1965) Photosensitized inactivation of nucleic acids in the presence of riboflavin. Biochim Biophys Acta.103:360-363. https://doi.org/10.1016/0005-2787(65)90182-6
  • 69 Corbin F 3rd. (2002) Pathogen inactivation of blood components: Current status and introduction of an approach using riboflavin as a photosensitizer. Int J Hematol 76 Suppl 2:253-257. https://doi.org/10.1007/bf03165125
  • 70 Averianova LA, Balabanova LA, Son OM, Podvolotskaya AB, Tekutyeva LA (2020) Production of Vitamin B2 (Riboflavin) by Microorganisms: An Overview. Front Bioeng Biotechnol 8:570828. https://doi.org/10.3389/fbioe.2020.570828
  • 71 Dakora FD, Matiru VN, Kanu AS (2015) Rhizosphere ecology of lumichrome and riboflavin, two bacterial signal molecules eliciting developmental changes in plants. Front Plant Sci 6:700. https://doi.org/10.3389/fpls.2015.00700
  • 72 Liu B, Liu Y, Yang B, Wang Q, Liu X, Qin J, Zhao K, Li F, Feng X, Li L, Wu P, Liu M, Zhu S, Feng L, Wang L (2022) Escherichia coli O157:H7 senses microbiota-produced riboflavin to increase its virulence in the gut. Proc Natl Acad Sci U S A 119:e2212436119. https://doi.org/10.1073/pnas.2212436119
  • 73 Kucharewicz-Krukowska A, Ślopek S (1987) Immunogenic effect of bacteriophage in patients subjected to phage therapy. Arch Immunol Ther Exp (Warsz) 35:553-561.
  • 74 Bruttin A, Brüssow H (2005) Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother 49:2874-2878. https://doi.org/10.1128/aac.49.7.2874-2878.2005
  • 75 Górski A, Międzybrodzki R, Borysowski J, Dąbrowska K, Wierzbicki P, Ohams M, Korczak-Kowalska G, Olszowska-Zaremba N, Łusiak-Szelachowska M, Kłak M, Jończyk E, Kaniuga E, Gołaś A, Purchla S, Weber-Dąbrowska B, Letkiewicz S, Fortuna W, Szufnarowski K, Pawełczyk Z, Rogóż P, Kłosowska D (2012) Phage as a modulator of immune responses: practical implications for phage therapy. Adv Virus Res 83:41-71. https://doi.org/10.1016/b978-0-12-394438-2.00002-5
  • 76 Stashak PW, Baker PJ, Roberson BS (1970) The serum antibody response to bacteriophage phiX174 in germ-free and conventionally reared mice. Immunology 18: 295-305.
  • 77 Sulakvelidze A, Barrow P (2005) Phage therapy in animals and agribusiness. In: Kutter E, Sulakvelidze A (eds) Bacteriophages. Biology and Applications. CRC Press, Boca Raton, FL, pp 335-380.
  • 78 Krut O, Bekeredjian-Ding I (2018) Contribution of the immune response to phage therapy. J Immunol 200:3037-3044. https://doi.org/10.4049/jimmunol.1701745
  • 79 Mayneris-Perxachs J, Castells-Nobau A, Arnoriaga-Rodríguez M, Garre-Olmo J, Puig J, Ramos R, Martínez-Hernández F, Burokas A, Coll C, Moreno-Navarrete JM, Zapata-Tona C, Pedraza S, Pérez-Brocal V, Ramió-Torrentà L, Ricart W, Moya A, Martínez-García M, Maldonado R, Fernández-Real JM (2022) Caudovirales bacteriophages are associated with improved executive function and memory in flies, mice, and humans. Cell Host Microbe 30:340-356.e8. https://doi.org/10.1016/j.chom.2022.01.013
  • 80 Slopek S, Weber-Dabrowska B, Dabrowski M, Kucharewicz-Krukowska A (1987) Results of bacteriophage treatment of suppurative bacterial infections in the years 1981–1986. Arch Immunol Ther Exp (Warsz) 35:569-583
  • 81 Majewska J, Beta W, Lecion D, Hodyra-Stefaniak K, Kłopot A, Kaz´mierczak Z, Miernikiewicz P, Piotrowicz A, Ciekot J, Owczarek B, Kopciuch A, Wojtyna K, Harhala M, Ma˛kosa M, Da˛browska K (2015) Oral application of T4 phage induces weak antibody production in the gut and in the blood. Viruses 7:4783-4799. https://doi.org/10.3390/v7082845
  • 82 Li SK, Leung RK, Guo HX, Wei JF, Wang JH, Kwong KT, Lee SS, Zhang C, Tsui SK (2012) Detection and identification of plasma bacterial and viral elements in HIV/AIDS patients in comparison to healthy adults, Clin Microbiol Infect 18:1126-1133. https://doi.org/10.1111/j.1469-0691.2011.03690.x
  • 83 Dinakaran V, Rathinavel A, Pushpanathan M, Sivakumar R, Gunasekaran P, Rajendhran J (2014) Elevated levels of circulating DNA in cardiovascular disease patients: metagenomic profiling of microbiome in the circulation. PLoS One 9:e105221. https://doi.org/10.1371/journal.pone.0105221
  • 84 Beauchamp S (2019) The impact of bacteriophage on the aging brain and inflammatory response: Relevance to Parkinson's disease. Dissertation, Carleton University https://repository.library.carleton.ca/concern/etds/wh246t184 https://doi.org/10.22215/etd/2019-13811