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Open Access 01-12-2023 | Antibiotic | Research

The persistence and stabilization of auxiliary genes in the human skin virome

Authors: Ema H. Graham, Wesley A. Tom, Alison C. Neujahr, Michael S. Adamowicz, Jennifer L. Clarke, Joshua R. Herr, Samodha C. Fernando

Published in: Virology Journal | Issue 1/2023

Abstract

Background

The human skin contains a diverse microbiome that provides protective functions against environmental pathogens. Studies have demonstrated that bacteriophages modulate bacterial community composition and facilitate the transfer of host-specific genes, potentially influencing host cellular functions. However, little is known about the human skin virome and its role in human health. Especially, how viral-host relationships influence skin microbiome structure and function is poorly understood.

Results

Population dynamics and genetic diversity of bacteriophage communities in viral metagenomic data collected from three anatomical skin locations from 60 subjects at five different time points revealed that cutaneous bacteriophage populations are mainly composed of tailed Caudovirales phages that carry auxiliary genes to help improve metabolic remodeling to increase bacterial host fitness through antimicrobial resistance. Sequence variation in the MRSA associated antimicrobial resistance gene, erm(C) was evaluated using targeted sequencing to further confirm the presence of antimicrobial resistance genes in the human virome and to demonstrate how functionality of such genes may influence persistence and in turn stabilization of bacterial host and their functions.

Conclusions

This large temporal study of human skin associated viruses indicates that the human skin virome is associated with auxiliary metabolic genes and antimicrobial resistance genes to help increase bacterial host fitness.

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Breitbart M, Bonnain C, Malki K, Sawaya NA. Phage puppet masters of the marine microbial realm. Nat Microbiol. 2018;3:754–66.PubMedCrossRef

Suttle CA. Marine viruses—major players in the global ecosystem. Nat Rev Microbiol. 2007;5:801–12.PubMedCrossRef

Breitbart M. Marine viruses: truth or dare. Ann Rev Mar Sci. 2012;4:425–48.PubMedCrossRef

Chaturongakul S, Ounjai P. Phage-host interplay: examples from tailed phages and gram-negative bacterial pathogens. Front Microbiol. 2014. https://doi.org/10.3389/fmicb.2014.00442.CrossRefPubMedPubMedCentral

Von Wintersdorff CJH, Penders J, Van Niekerk JM, Mills ND, Majumder S, Van Alphen LB, et al. Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer. Front Microbiol. 2016. https://doi.org/10.3389/fmicb.2016.00173.CrossRef

Hay ID, Lithgow T. Filamentous phages: masters of a microbial sharing economy. EMBO Rep. 2019. https://doi.org/10.15252/embr.201847427.CrossRefPubMedPubMedCentral

Sutton TDS, Hill C. Gut bacteriophage: current understanding and challenges. Front Endocrinol (Lausanne). 2019. https://doi.org/10.3389/fendo.2019.00784.CrossRefPubMed

Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018;16:143–55.PubMedCrossRef

Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med. 2018;24:392–400.PubMedPubMedCentralCrossRef

10.

Derbise A, Chenal-Francisque V, Pouillot F, Fayolle C, Prévost MC, Médigue C, et al. A horizontally acquired filamentous phage contributes to the pathogenicity of the plague bacillus. Mol Microbiol. 2007;63:1145–57.PubMedCrossRef

11.

Rice SA, Tan CH, Mikkelsen PJ, Kung V, Woo J, Tay M, et al. The biofilm life cycle and virulence of Pseudomonas aeruginosa are dependent on a filamentous prophage. ISME J. 2009;3:271–82.PubMedCrossRef

12.

Faruque SM, Mekalanos JJ. Phage-bacterial interactions in the evolution of toxigenic Vibrio cholerae. Virulence. 2012;3:556–65.PubMedPubMedCentralCrossRef

13.

Huang X, Jiao N, Zhang R. The genomic content and context of auxiliary metabolic genes in roseophages. Environ Microbiol. 2021;23:3743–57.PubMedCrossRef

14.

Kieft K, Zhou Z, Anderson RE, Buchan A, Campbell BJ, Hallam SJ, et al. Ecology of inorganic sulfur auxiliary metabolism in widespread bacteriophages. Nat Commun. 2021;12:3503.PubMedPubMedCentralCrossRef

15.

Lindell D, Jaffe JD, Johnson ZI, Church GM, Chisholm SW. Photosynthesis genes in marine viruses yield proteins during host infection. Nature. 2005;438:86–9.PubMedCrossRef

16.

Byrd AL, Deming C, Cassidy SKB, Harrison OJ, Ng WI, Conlan S, et al. Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med. 2017;9(397):eaal4651.PubMedPubMedCentralCrossRef

17.

Hannigan GD, Meisel JS, Tyldsley AS, Zheng Q, Hodkinson BP, Sanmiguel AJ, et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. MBio. 2015;6:e01578.PubMedPubMedCentralCrossRef

18.

Oh J, Byrd AL, Park M, Kong HH, Segre JA. Temporal stability of the human skin microbiome. Cell. 2016;165:854–66.PubMedPubMedCentralCrossRef

19.

van Zyl LJ, Abrahams Y, Stander EA, Kirby-McCollough B, Jourdain R, Clavaud C, et al. Novel phages of healthy skin metaviromes from South Africa. Sci Rep. 2018;8:12265.PubMedPubMedCentralCrossRef

20.

Tisza MJ, Buck CB. A catalog of tens of thousands of viruses from human metagenomes reveals hidden associations with chronic diseases. Proc Natl Acad Sci. 2021;118:e2023202118.PubMedPubMedCentralCrossRef

21.

Furfaro LL, Payne MS, Chang BJ. Bacteriophage therapy: clinical trials and regulatory hurdles. Front Cell Infect Microbiol. 2018. https://doi.org/10.3389/fcimb.2018.00376.CrossRefPubMedPubMedCentral

22.

Castillo DE, Nanda S, Keri JE. Propionibacterium (Cutibacterium) acnes bacteriophage therapy in acne: current evidence and future perspectives. Dermatol Ther (Heidelb). 2019;9:19–31.PubMedCrossRef

23.

Brives C, Pourraz J. Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures. Palgrave Commun. 2020;6:100.CrossRef

24.

Pirnay JP. Phage therapy in the year 2035. Front Microbiol. 2020. https://doi.org/10.3389/fmicb.2020.01171.CrossRefPubMedPubMedCentral

25.

Kieft K, Breister AM, Huss P, Linz AM, Zanetakos E, Zhou Z, et al. Virus-associated organosulfur metabolism in human and environmental systems. Cell Rep. 2021;36:109471.PubMedCrossRef

26.

Graham EH, Clarke JL, Fernando SC, Herr JR, Adamowicz MS. The application of the skin virome for human identification. Forensic Sci Int Genet. 2022;57:102662.PubMedCrossRef

27.

Bushnell B. BBMap: a fast, accurate, splice-aware aligner. 2014. [https://www.osti.gov/servlets/purl/1241166].

28.

Roux S, Krupovic M, Debroas D, Forterre P, Enault F. Assessment of viral community functional potential from viral metagenomes may be hampered by contamination with cellular sequences. Open Biol. 2013;3:130160.PubMedPubMedCentralCrossRef

29.

Li D, Liu CM, Luo R, Sadakane K, Lam TW. MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics. 2015;31:1674–6.PubMedCrossRef

30.

Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. 2013. [http://arxiv.org/abs/1303.3997].

31.

Kieft K, Zhou Z, Anantharaman K. VIBRANT: automated recovery, annotation and curation of microbial viruses, and evaluation of viral community function from genomic sequences. Microbiome. 2020;8:90.PubMedPubMedCentralCrossRef

32.

Menzel P, Ng KL, Krogh A. Fast and sensitive taxonomic classification for metagenomics with Kaiju. Nat Commun. 2016;7:11257.PubMedPubMedCentralCrossRef

33.

Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.PubMedPubMedCentralCrossRef

34.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25:2078–9.PubMedPubMedCentralCrossRef

35.

The CRAN R Team: R: a language and environment for statistical computing. R Found Stat Comput. 2013.

36.

Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.PubMedCrossRef

37.

Doster E, Lakin SM, Dean CJ, Wolfe C, Young JG, Boucher C, et al. MEGARes 2.0: a database for classification of antimicrobial drug, biocide and metal resistance determinants in metagenomic sequence data. Nucleic Acids Res. 2020;48:D561–9.PubMedCrossRef

38.

Enault F, Briet A, Bouteille L, Roux S, Sullivan MB, Petit MA. Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. ISME J. 2017;11:237–47.PubMedCrossRef

39.

Shannon CE. A mathematical theory of communication. Bell Syst Tech J. 1948;27:379–423.CrossRef

40.

Simpson EH. Measurement of diversity. Nature. 1949;163:688.CrossRef

41.

Oksanen J. Vegan: community ecology package. 2020. [https://cran.r-project.org/package=vegan].

42.

Odintsova V, Tyakht A, Alexeev D. Guidelines to statistical analysis of microbial composition data inferred from metagenomic sequencing. Curr Issues Mol Biol. 2017;24:17–36.PubMedCrossRef

43.

Strommenger B, Kettlitz C, Werner G, Witte W. Multiplex PCR assay for simultaneous detection of nine clinically relevant antibiotic resistance genes in Staphylococcus aureus. J Clin Microbiol. 2003;41:4089–94.PubMedPubMedCentralCrossRef

44.

Kozich JJ, Westcott SL, Baxter NT, Highlander SK, Schloss PD. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the miseq illumina sequencing platform. Appl Environ Microbiol. 2013;79:5112–20.PubMedPubMedCentralCrossRef

45.

Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3.PubMedPubMedCentralCrossRef

46.

Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004;32:1792–7.PubMedPubMedCentralCrossRef

47.

Nguyen LT, Schmidt HA, Von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol. 2015;32:268–74.PubMedCrossRef

48.

Letunic I, Bork P. Interactive tree of life (iTOL) v5: an online tool for phylogenetic tree display and annotation. Nucleic Acids Res. 2021;49:W293–6.PubMedPubMedCentralCrossRef

49.

Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31:2745–7.PubMedPubMedCentralCrossRef

50.

Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.PubMedPubMedCentralCrossRef

51.

Ittisoponpisan S, Islam SA, Khanna T, Alhuzimi E, David A, Sternberg MJE. Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated? J Mol Biol. 2019;431:2197–212.PubMedPubMedCentralCrossRef

52.

Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modeling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–303.PubMedPubMedCentralCrossRef

53.

Bienert S, Waterhouse A, De Beer TAP, Tauriello G, Studer G, Bordoli L, et al. The SWISS-MODEL repository-new features and functionality. Nucleic Acids Res. 2017;45:D313–9.PubMedCrossRef

54.

Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45:D353–61.PubMedCrossRef

55.

Hall AR, Scanlan PD, Morgan AD, Buckling A. Host-parasite coevolutionary arms races give way to fluctuating selection. Ecol Lett. 2011;14:635–42.PubMedCrossRef

56.

Stone E, Campbell K, Grant I, McAuliffe O. Understanding and exploiting phage–host interactions. Viruses. 2019;11:567.PubMedPubMedCentralCrossRef

57.

Anderson CL, Sullivan MB, Fernando SC. Dietary energy drives the dynamic response of bovine rumen viral communities. Microbiome. 2017;5:155.PubMedPubMedCentralCrossRef

58.

Willner D, Furlan M, Haynes M, Schmieder R, Angly FE, Silva J, et al. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS ONE. 2009;4: e7370.PubMedPubMedCentralCrossRef

59.

Foulongne V, Sauvage V, Hebert C, Dereure O, Cheval J, Gouilh MA, et al. Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLoS ONE. 2012;7: e38499.PubMedPubMedCentralCrossRef

60.

Abbas AA, Diamond JM, Chehoud C, Chang B, Kotzin JJ, Young JC, et al. The perioperative lung transplant virome: torque teno viruses are elevated in donor lungs and show divergent dynamics in primary graft dysfunction. Am J Transplant. 2017;17:1313–24.PubMedCrossRef

61.

Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y, et al. The blood DNA virome in 8,000 humans. PLOS Pathog. 2017;13:e1006292.PubMedPubMedCentralCrossRef

62.

Tirosh O, Conlan S, Deming C, Lee-Lin SQ, Huang X, Barnabas BB, et al. Expanded skin virome in DOCK8-deficient patients. Nat Med. 2018;24:1815–21.PubMedPubMedCentralCrossRef

63.

Garretto A, Miller-Ensminger T, Wolfe AJ, Putonti C. Bacteriophages of the lower urinary tract. Nat Rev Urol. 2019;16:422–32.PubMedPubMedCentralCrossRef

64.

Ghose C, Ly M, Schwanemann LK, Shin JH, Atab K, Barr JJ, et al. The virome of cerebrospinal fluid: viruses where we once thought there were none. Front Microbiol. 2019. https://doi.org/10.3389/fmicb.2019.02061.CrossRefPubMedPubMedCentral

65.

Jakobsen RR, Haahr T, Humaidan P, Jensen JS, Kot WP, Castro-Mejia JL, et al. Characterization of the vaginal DNA virome in health and dysbiosis. Viruses. 2020;12:1143.PubMedPubMedCentralCrossRef

66.

Liang G, Bushman FD. The human virome: assembly, composition and host interactions. Nat Rev Microbiol. 2021;19:514–27.PubMedPubMedCentralCrossRef

67.

Malik SS, Azem-e-Zahra S, Kim KM, Caetano-Anollés G, Nasir A. Do viruses exchange genes across superkingdoms of life? Front Microbiol. 2017;8:2110.PubMedPubMedCentralCrossRef

68.

Weiss RA. Exchange of genetic sequences between viruses and hosts. Curr Top Microbiol Immunol. 2017;407:1–29.PubMed

69.

Zhang Y, Guo R, Kim SH, Shah H, Zhang S, Liang JH, et al. SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication. Nat Commun. 2021;12:1676.PubMedPubMedCentralCrossRef

70.

Reygaert CW. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol. 2018;4:482–501.PubMedPubMedCentralCrossRef

71.

Chancey ST, Zhou X, Zähner D, Stephens DS. Induction of efflux-mediated macrolide resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2011;55:3413–22.PubMedPubMedCentralCrossRef

72.

Daly MM, Doktor S, Flamm R, Shortridge D. Characterization and prevalence of MefA, MefE, and the associated msr(D) gene in Streptococcus pneumoniae clinical isolates. J Clin Microbiol. 2004;42:3570–4.PubMedPubMedCentralCrossRef

73.

Giovanetti E, Brenciani A, Vecchi M, Manzin A, Varaldo PE. Prophage association of mef(A) elements encoding efflux-mediated erythromycin resistance in Streptococcus pyogenes. J Antimicrob Chemother. 2005;55:445–51.PubMedCrossRef

74.

Iannelli F, Santagati M, Santoro F, Oggioni MR, Stefani S, Pozzi G. Nucleotide sequence of conjugative prophage Φ1207.3 (formerly Tn1207.3) carrying the mef(A)/msr(D) genes for efflux resistance to macrolides in Streptococcus pyogenes. Front Microbiol. 2014. https://doi.org/10.3389/fmicb.2014.00687.CrossRefPubMedPubMedCentral

75.

Chancey ST, Bai X, Kumar N, Drabek EF, Daugherty SC, Colon T, et al. Transcriptional attenuation controls macrolide inducible efflux and resistance in Streptococcus pneumoniae and in other gram-positive bacteria containing mef/mel (msr(D)) elements. PLoS ONE. 2015;10:e0116254.PubMedPubMedCentralCrossRef

76.

Tandukar M, Oh S, Tezel U, Konstantinidis KT, Pavlostathis SG. Long-term exposure to benzalkonium chloride disinfectants results in change of microbial community structure and increased antimicrobial resistance. Environ Sci Technol. 2013;47:9730–8.PubMedCrossRef

77.

Li X, Rensing C, Vestergaard G, Arumugam M, Nesme J, Gupta S, et al. Metagenomic evidence for co-occurrence of antibiotic, biocide and metal resistance genes in pigs. Environ Int. 2022;158:106899.PubMedCrossRef

78.

Spiliopoulou I, Petinaki E, Papandreou P, Dimitracopoulos G. Erm(C) is the predominant genetic determinant for the expression of resistance to macrolides among methicillin-resistant Staphylococcus aureus clinical isolates in Greece. J Antimicrob Chemother. 2004;53:814–7.PubMedCrossRef

Title: The persistence and stabilization of auxiliary genes in the human skin virome
Authors: Ema H. Graham
Wesley A. Tom
Alison C. Neujahr
Michael S. Adamowicz
Jennifer L. Clarke
Joshua R. Herr
Samodha C. Fernando
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Antibiotic
Published in: Virology Journal / Issue 1/2023
Electronic ISSN: 1743-422X
DOI: https://doi.org/10.1186/s12985-023-02012-3

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