1887

Abstract

Phase-variable DNA methyltransferases control the expression of multiple genes via epigenetic mechanisms in a wide variety of bacterial species. These systems are called phasevarions, for phase-variable regulons. Phasevarions regulate genes involved in pathogenesis, host adaptation and antibiotic resistance. Many human-adapted bacterial pathogens contain phasevarions. These include leading causes of morbidity and mortality worldwide, such as non-typeable , and spp. Phase-variable methyltransferases and phasevarions have also been discovered in environmental organisms and veterinary pathogens. The existence of many different examples suggests that phasevarions have evolved multiple times as a contingency strategy in the bacterial domain, controlling phenotypes that are important in adapting to environmental change. Many of the organisms that contain phasevarions have existing or emerging drug resistance. Vaccines may therefore represent the best and most cost-effective tool to prevent disease caused by these organisms. However, many phasevarions also control the expression of current and putative vaccine candidates; variable expression of antigens could lead to immune evasion, meaning that vaccines designed using these targets become ineffective. It is therefore essential to characterize phasevarions in order to determine an organism’s stably expressed antigenic repertoire, and rationally design broadly effective vaccines.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000805
2019-09-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/micro/165/9/917.html?itemId=/content/journal/micro/10.1099/mic.0.000805&mimeType=html&fmt=ahah

References

  1. Dupont C, Armant D, Brenner C. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 2009; 27:351–357 [View Article]
    [Google Scholar]
  2. Blow MJ, Clark TA, Daum CG, Deutschbauer AM, Fomenkov A et al. The epigenomic landscape of prokaryotes. PLoS Genet 2016; 12:e1005854 [View Article]
    [Google Scholar]
  3. Adhikari S, Curtis PD. DNA methyltransferases and epigenetic regulation in bacteria. FEMS Microbiology Reviews 2016; 40:575–591 [View Article]
    [Google Scholar]
  4. Casadesús J, Low DA. Programmed heterogeneity: epigenetic mechanisms in bacteria. J Biol Chem 2013; 288:13929–13935 [View Article]
    [Google Scholar]
  5. Casadesús J, Low D. Epigenetic gene regulation in the bacterial world. Microbiol Mol Biol Rev 2006; 70:830–856 [View Article]
    [Google Scholar]
  6. Bickle TA, Krüger DH. Biology of DNA restriction. Microbiol Rev 1993; 57:434–450
    [Google Scholar]
  7. Vasu K, Nagaraja V. Diverse functions of restriction-modification systems in addition to cellular defense. Microbiol Mol Biol Rev 2013; 77:53–72 [View Article]
    [Google Scholar]
  8. Roberts RJ, Belfort M, Bestor T, Bhagwat AS, Bickle TA et al. A Nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes. Nucleic Acids Res 2003; 31:1805–1812 [View Article]
    [Google Scholar]
  9. Loenen WAM, Dryden DTF, Raleigh EA, Wilson GG. Type I restriction enzymes and their relatives. Nucleic Acids Res 2014; 42:20–44 [View Article]
    [Google Scholar]
  10. Pingoud A, Wilson GG, Wende W. Type II restriction endonucleases-a historical perspective and more. Nucleic Acids Res 2014; 42:7489–7527 [View Article]
    [Google Scholar]
  11. Bourniquel AA, Bickle TA. Complex restriction enzymes: NTP-driven molecular motors. Biochimie 2002; 84:1047–1059 [View Article]
    [Google Scholar]
  12. Raghavendra NK, Bheemanaik S, Rao DN. Mechanistic insights into type III restriction enzymes. Front Biosci 2012; 17:1094–1107 [View Article]
    [Google Scholar]
  13. Rao DN, Dryden DTF, Bheemanaik S. Type III restriction-modification enzymes: a historical perspective. Nucleic Acids Res 2014; 42:45–55 [View Article]
    [Google Scholar]
  14. Loenen WAM, Raleigh EA. The other face of restriction: modification-dependent enzymes. Nucleic Acids Res 2014; 42:56–69 [View Article]
    [Google Scholar]
  15. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33:245–254 [View Article]
    [Google Scholar]
  16. Krueger F, Kreck B, Franke A, Andrews SR. DNA methylome analysis using short bisulfite sequencing data. Nat Methods 2012; 9:145–151 [View Article]
    [Google Scholar]
  17. Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 2005; 37:853–862 [View Article]
    [Google Scholar]
  18. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 1996; 93:9821–9826 [View Article]
    [Google Scholar]
  19. Adamczyk-Poplawska M, Lower M, Piekarowicz A. Deletion of one nucleotide within the homonucleotide tract present in the hsdS gene alters the DNA sequence specificity of type I restriction-modification system NgoAV. J Bacteriol 2011; 193:6750–6759 [View Article]
    [Google Scholar]
  20. Srikhanta YN, Dowideit SJ, Edwards JL, Falsetta ML, Wu H-J et al. Phasevarions mediate random switching of gene expression in pathogenic Neisseria . PLoS Pathog 2009; 5:e1000400 [View Article]
    [Google Scholar]
  21. Dohno C, Shibata T, Nakatani K. Discrimination of N6-methyl adenine in a specific DNA sequence. Chem. Commun. 2010; 46:5530 [View Article]
    [Google Scholar]
  22. Adamczyk-Poplawska M, Lower M, Piekarowicz A. Characterization of the NgoAXP: phase-variable type III restriction-modification system in Neisseria gonorrhoeae . FEMS Microbiol Lett 2009; 300:25–35 [View Article]
    [Google Scholar]
  23. Beaulaurier J, Schadt EE, Fang G. Deciphering bacterial epigenomes using modern sequencing technologies. Nature Reviews Genetics 2018
    [Google Scholar]
  24. Rand AC, Jain M, Eizenga JM, Musselman-Brown A, Olsen HE et al. Mapping DNA methylation with high-throughput nanopore sequencing. Nat Methods 2017; 14:411–413 [View Article]
    [Google Scholar]
  25. Flusberg BA, Webster DR, Lee JH, Travers KJ, Olivares EC et al. Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat Methods 2010; 7:461–465 [View Article]
    [Google Scholar]
  26. Clark TA, Murray IA, Morgan RD, Kislyuk AO, Spittle KE et al. Characterization of DNA methyltransferase specificities using single-molecule, real-time DNA sequencing. Nucleic Acids Res 2012; 40:e29 [View Article]
    [Google Scholar]
  27. Korlach J, Bjornson KP, Chaudhuri BP, Cicero RL, Flusberg BA et al. Real-time DNA sequencing from single polymerase molecules. Methods Enzymol 2010; 472:431–455 [View Article]
    [Google Scholar]
  28. Beaulaurier J, Zhang X-S, Zhu S, Sebra R, Rosenbluh C et al. Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes. Nat Commun 2015; 6:7438 [View Article]
    [Google Scholar]
  29. Davis BM, Chao MC, Waldor MK. Entering the era of bacterial epigenomics with single molecule real time DNA sequencing. Curr Opin Microbiol 2013; 16:192–198 [View Article]
    [Google Scholar]
  30. Atack JM, Tan A, Bakaletz LO, Jennings MP, Seib KL. Phasevarions of bacterial pathogens: methylomics sheds new light on old enemies. Trends Microbiol 2018; 26:715–726 [View Article]
    [Google Scholar]
  31. Murray IA, Clark TA, Morgan RD, Boitano M, Anton BP et al. The methylomes of six bacteria. Nucleic Acids Res 2012; 40:11450–11462 [View Article]
    [Google Scholar]
  32. Forde BM, Phan M-D, Gawthorne JA, Ashcroft MM, Stanton-Cook M et al. Lineage-specific methyltransferases define the methylome of the globally disseminated Escherichia coli ST131 Clone. MBio 2015; 6:e01602–01615 [View Article]
    [Google Scholar]
  33. Krebes J, Morgan RD, Bunk B, Spröer C, Luong K et al. The complex methylome of the human gastric pathogen Helicobacter pylori . Nucleic Acids Res 2014; 42:2415–2432 [View Article]
    [Google Scholar]
  34. Gorrell R, Kwok T. The Helicobacter pylori methylome: roles in gene regulation and virulence. In Tegtmeyer N, Backert S. (editors) Molecular Pathogenesis and Signal Transduction by Helicobacter pylori Cham: Springer International Publishing; 2017 pp 105–127
    [Google Scholar]
  35. Payelleville A, Legrand L, Ogier J-C, Roques C, Roulet A et al. The complete methylome of an entomopathogenic bacterium reveals the existence of loci with unmethylated adenines. Sci Rep 2018; 8:12091 [View Article]
    [Google Scholar]
  36. Atack JM, Srikhanta YN, Fox KL, Jurcisek JA, Brockman KL et al. A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae . Nat Commun 2015; 6:7828 [View Article]
    [Google Scholar]
  37. Blakeway LV, Power PM, Jen FE-C, Worboys SR, Boitano M et al. ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media. FASEB J 2014; 28:5197–5207 [View Article]
    [Google Scholar]
  38. Seib KL, Jen FE-C, Tan A, Scott AL, Kumar R et al. Specificity of the ModA11, ModA12 and ModD1 epigenetic regulator N(6)-adenine DNA methyltransferases of Neisseria meningitidis . Nucleic Acids Res 2015; 43:4150–4162 [View Article]
    [Google Scholar]
  39. Manso AS, Chai MH, Atack JM, Furi L, De Ste Croix M et al. A random six-phase switch regulates pneumococcal virulence via global epigenetic changes. Nat Commun 2014; 5:5055 [View Article]
    [Google Scholar]
  40. Tan A, Atack JM, Jennings MP, Seib KL. The capricious nature of bacterial pathogens: Phasevarions and vaccine development. Front Immunol 2016; 7:586 [View Article]
    [Google Scholar]
  41. Moxon R, Bayliss C, Hood D. Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. Annu Rev Genet 2006; 40:307–333 [View Article]
    [Google Scholar]
  42. Atack JM, Winter LE, Jurcisek JA, Bakaletz LO, Barenkamp SJ et al. Selection and counterselection of hia expression reveals a key role for phase-variable expression of hia in infection caused by nontypeable Haemophilus influenzae . J Infect Dis 2015; 212:645–653 [View Article]
    [Google Scholar]
  43. Blyn LB, Braaten BA, Low DA. Regulation of pap pilin phase variation by a mechanism involving differential dam methylation states. Embo J 1990; 9:4045–4054 [View Article]
    [Google Scholar]
  44. Richardson AR, Stojiljkovic I, HmbR SI. HmbR, a hemoglobin-binding outer membrane protein of Neisseria meningitidis, undergoes phase variation. J Bacteriol 1999; 181:2067–2074
    [Google Scholar]
  45. Ren Z, Jin H, Whitby PW, Morton DJ, Stull TL. Role of CCAA nucleotide repeats in regulation of hemoglobin and hemoglobin-haptoglobin binding protein genes of Haemophilus influenzae . J Bacteriol 1999; 181:5865–5870
    [Google Scholar]
  46. Fox KL, Atack JM, Srikhanta YN, Eckert A, Novotny LA et al. Selection for phase variation of LOS biosynthetic genes frequently occurs in progression of non-typeable Haemophilus influenzae infection from the nasopharynx to the middle ear of human patients. PLoS One 2014; 9:e90505 [View Article]
    [Google Scholar]
  47. Poole J, Foster E, Chaloner K, Hunt J, Jennings MP et al. Analysis of nontypeable Haemophilus influenzae phase-variable genes during experimental human nasopharyngeal colonization. J Infect Dis 2013; 208:720–727 [View Article]
    [Google Scholar]
  48. Srikhanta YN, Fox KL, Jennings MP. The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes. Nat Rev Microbiol 2010; 8:196–206 [View Article]
    [Google Scholar]
  49. Dybvig K, Sitaraman R, French CT. A family of phase-variable restriction enzymes with differing specificities generated by high-frequency gene rearrangements. Proc Natl Acad Sci U S A 1998; 95:13923–13928 [View Article]
    [Google Scholar]
  50. Haigh RD, Crawford LA, Ralph JD, Wanford JJ, Vartoukian SR et al. Draft whole-genome sequences of periodontal pathobionts Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia contain phase-variable restriction-modification systems. Genome Announc 2017; 5:e01229–17 [View Article]
    [Google Scholar]
  51. Chen P, den Bakker HC, Korlach J, Kong N, Storey DB et al. Comparative genomics reveals the diversity of restriction-modification systems and DNA methylation sites in Listeria monocytogenes . Appl Environ Microbiol 2017; 83:e02091–16 [View Article]
    [Google Scholar]
  52. De Ste Croix M, Vacca I, Kwun MJ, Ralph JD, Bentley SD et al. Phase-variable methylation and epigenetic regulation by type I restriction-modification systems. FEMS Microbiol Rev 2017; 41:S3–S15 [View Article]
    [Google Scholar]
  53. Vos T, Allen C, Arora M, Barber RM, Bhutta ZA et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of Disease Study 2015. The Lancet 2016; 388:1545–1602 [View Article]
    [Google Scholar]
  54. Li J, Li J-W, Feng Z, Wang J, An H et al. Epigenetic switch driven by DNA inversions dictates phase variation in Streptococcus pneumoniae . PLoS Pathog 2016; 12:e1005762 [View Article]
    [Google Scholar]
  55. JW L, Li J, Wang J, Li C, Zhang JR. Molecular mechanisms of hsdS inversions in the cod locus of Streptococcus pneumoniae . J Bacteriol 2019
    [Google Scholar]
  56. Oliver MB, Basu Roy A, Kumar R, Lefkowitz EJ, Swords WE. Streptococcus pneumoniae TIGR4 phase-locked opacity variants differ in virulence phenotypes. mSphere 2017; 2:15 11 2017 [View Article]
    [Google Scholar]
  57. Gottschalk M. Streptococcosis. In Zimmerman J, Karriker L, Rameriz A, Schwartz K. (editors) Diseases of Swine 10 Ames, IA: Wiley-Blackwell; 2010 pp 841–855
    [Google Scholar]
  58. Wertheim HFL, Nghia HDT, Taylor W, Schultsz C. Streptococcus suis: an emerging human pathogen. Clin Infect Dis 2009; 48:617–625 [View Article]
    [Google Scholar]
  59. Tang J, Wang C, Feng Y, Yang W, Song H et al. Streptococcal toxic shock syndrome caused by Streptococcus suis serotype 2. PLoS Med 2006; 3:e151 [View Article]
    [Google Scholar]
  60. Atack JM, Weinert LA, Tucker AW, Husna AU, Wileman TM et al. Streptococcus suis contains multiple phase-variable methyltransferases that show a discrete lineage distribution. Nucleic Acids Res 2018; 48: [View Article]
    [Google Scholar]
  61. Weinert LA, Chaudhuri RR, Wang J, Peters SE, Corander J et al. Genomic signatures of human and animal disease in the zoonotic pathogen Streptococcus suis . Nat Commun 2015; 6:
    [Google Scholar]
  62. MacFadden DR, Lipsitch M, Olesen SW, Grad Y. Multidrug-resistant Neisseria gonorrhoeae: implications for future treatment strategies. Lancet Infect Dis 2018; 18:599 [View Article]
    [Google Scholar]
  63. Zaleski P, Wojciechowski M, Piekarowicz A. The role of Dam methylation in phase variation of Haemophilus influenzae genes involved in defence against phage infection. Microbiology 2005; 151:3361–3369 [View Article]
    [Google Scholar]
  64. Highlander SK, Garza O. The restriction-modification system of Pasteurella haemolytica is a member of a new family of type I enzymes. Gene 1996; 178:89–96 [View Article]
    [Google Scholar]
  65. Atack JM, Yang Y, Seib KL, Zhou Y, Jennings MP. A survey of Type III restriction-modification systems reveals numerous, novel epigenetic regulators controlling phase-variable regulons; phasevarions. Nucleic Acids Res 2018; 46:3532–3542 [View Article]
    [Google Scholar]
  66. Gawthorne JA, Beatson SA, Srikhanta YN, Fox KL, Jennings MP. Origin of the diversity in DNA recognition domains in phasevarion associated modA genes of pathogenic Neisseria and Haemophilus influenzae . PLoS One 2012; 7:e32337 [View Article]
    [Google Scholar]
  67. Srikhanta YN, Maguire TL, Stacey KJ, Grimmond SM, Jennings MP. The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes. Proc Natl Acad Sci U S A 2005; 102:5547–5551 [View Article]
    [Google Scholar]
  68. Bayliss CD, Field D, Moxon ER. The simple sequence contingency loci of Haemophilus influenzae and Neisseria meningitidis . J Clin Invest 2001; 107:657–666 [View Article]
    [Google Scholar]
  69. Fox KL, Dowideit SJ, Erwin AL, Srikhanta YN, Smith AL et al. Haemophilus influenzae phasevarions have evolved from type III DNA restriction systems into epigenetic regulators of gene expression. Nucleic Acids Res 2007; 35:5242–5252 [View Article]
    [Google Scholar]
  70. Seib KL, Pigozzi E, Muzzi A, Gawthorne JA, Delany I et al. A novel epigenetic regulator associated with the hypervirulent Neisseria meningitidis clonal complex 41/44. Faseb J 2011; 25:3622–3633 [View Article]
    [Google Scholar]
  71. Srikhanta YN, Gorrell RJ, Steen JA, Gawthorne JA, Kwok T et al. Phasevarion mediated epigenetic gene regulation in Helicobacter pylori . PLoS One 2011; 6:e27569 [View Article]
    [Google Scholar]
  72. Seib K, Peak IR, Jennings MP. Phase variable restriction–modification systems in Moraxella catarrhalis . FEMS Immunol Med Mic 2002; 32:159–165 [View Article]
    [Google Scholar]
  73. Murphy TF, Faden H, Bakaletz LO, Kyd JM, Forsgren A et al. Nontypeable Haemophilus influenzae as a pathogen in children. Pediatr Infect Dis J 2009; 28:43–48 [View Article]
    [Google Scholar]
  74. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008; 359:2355–2365 [View Article]
    [Google Scholar]
  75. Van Eldere J, Slack MPE, Ladhani S, Cripps AW. Non-typeable Haemophilus influenzae, an under-recognised pathogen. Lancet Infect Dis 2014; 14:1281–1292 [View Article]
    [Google Scholar]
  76. Johnson RH. Community-acquired pneumonia: etiology, diagnosis, and treatment. Clin Ther 1988; 10:568–573
    [Google Scholar]
  77. Langereis JD, de Jonge MI. Invasive disease caused by nontypeable Haemophilus influenzae . Emerg Infect Dis 2015; 21:1711–1718 [View Article]
    [Google Scholar]
  78. Agrawal A, Murphy TF. Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J Clin Microbiol 2011; 49:3728–3732 [View Article]
    [Google Scholar]
  79. Atack JM, Murphy TF, Bakaletz LO, Seib KL, Jennings MP. Closed complete genome sequences of two nontypeable Haemophilus influenzae strains containing novel moda alleles from the sputum of patients with chronic obstructive pulmonary disease. Microbiol Resour Announc 2018; 7:19 07 2018 [View Article]
    [Google Scholar]
  80. Brockman KL, Jurcisek JA, Atack JM, Srikhanta YN, Jennings MP et al. ModA2 phasevarion switching in nontypeable Haemophilus influenzae increases the severity of experimental otitis media. J Infect Dis 2016; 214:817–824 [View Article]
    [Google Scholar]
  81. Brockman KL, Branstool MT, Atack JM, Robledo-Avila F, Partida-Sanchez S et al. The ModA2 phasevarion of nontypeable Haemophilus influenzae regulates resistance to oxidative stress and killing by human neutrophils. Sci Rep 2017; 7:3161 [View Article]
    [Google Scholar]
  82. Brockman KL, Azzari PN, Branstool MT, Atack JM, Schulz BL et al. Epigenetic regulation alters biofilm architecture and composition in multiple clinical isolates of nontypeable Haemophilus influenzae . MBio 2018; 9: [View Article]
    [Google Scholar]
  83. Tan A, Hill DMC, Harrison OB, Srikhanta YN, Jennings MP et al. Distribution of the type III DNA methyltransferases modA, modB and modD among Neisseria meningitidis genotypes: implications for gene regulation and virulence. Sci Rep 2016; 6: [View Article]
    [Google Scholar]
  84. Jen FE-C, Seib KL, Jennings MP. Phasevarions mediate epigenetic regulation of antimicrobial susceptibility in Neisseria meningitidis . Antimicrob Agents Chemother 2014; 58:4219–4221 [View Article]
    [Google Scholar]
  85. Srikhanta YN, Gorrell RJ, Power PM, Tsyganov K, Boitano M et al. Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori . Sci Rep 2017; 7:16140 [View Article]
    [Google Scholar]
  86. Blakeway LV, Tan A, Lappan R, Ariff A, Pickering JL et al. Moraxella catarrhalis restriction-modification systems are associated with phylogenetic lineage and disease. Genome Biol Evol 2018; 10:2932–2946 [View Article]
    [Google Scholar]
  87. Hunt JM. Shiga toxin-producing Escherichia coli (STEC). Clin Lab Med 2010; 30:21–45 [View Article]
    [Google Scholar]
  88. Yagupsky P, Porsch E, St Geme JW. Kingella kingae: an emerging pathogen in young children. Pediatrics 2011; 127:557–565 [View Article]
    [Google Scholar]
  89. Srikhanta YN, Fung KY, Pollock GL, Bennett-Wood V, Howden BP et al. Phasevarion-regulated virulence in the emerging pediatric pathogen Kingella kingae . Infect Immun 2017; 85:e00319–17 [View Article]
    [Google Scholar]
  90. Dybvig K, Voelker LL. Molecular biology of mycoplasmas. Annu Rev Microbiol 1996; 50:25–57 [View Article]
    [Google Scholar]
  91. Algire MA, Montague MG, Vashee S, Lartigue C, Merryman C. A type III restriction-modification system in Mycoplasma mycoides subsp. Capri. Open Biol 2012; 2:120115 [View Article]
    [Google Scholar]
  92. Giuliani MM, Adu-Bobie J, Comanducci M, Aricò B, Savino S et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci U S A 2006; 103:10834–10839 [View Article]
    [Google Scholar]
  93. Fagnocchi L, Biolchi A, Ferlicca F, Boccadifuoco G, Brunelli B et al. Transcriptional regulation of the nadA gene in Neisseria meningitidis impacts the prediction of coverage of a multicomponent meningococcal serogroup B vaccine. Infect Immun 2013; 81:560–569 [View Article]
    [Google Scholar]
  94. Winter LE, Barenkamp SJ. Construction and immunogenicity of recombinant adenovirus vaccines expressing the HMW1, HMW2, or Hia adhesion protein of nontypeable Haemophilus influenzae . Clin Vaccine Immunol 2010; 17:1567–1575 [View Article]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000805
Loading
/content/journal/micro/10.1099/mic.0.000805
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error