Urogenit Tract Infect.  2017 Aug;12(2):65-76. 10.14777/uti.2017.12.2.65.

Genetic Variation in Mycoplasma genitalium

Affiliations
  • 1Department of Urology, Dankook University College of Medicine, Cheonan, Korea. multiorigins@yahoo.com

Abstract

Mycoplasma genitalium (MG) is the smallest self-replicating bacterium. Although small in size, unique MG genome induces distinctive and often serious characteristics in the infected cells. Due to its small genome and chronic symptomatic characteristics in the infected host, it first appears as a weak, insignificant, and easily controllable microbe. However, it is not a monotonous chrysalis, but rather a multicolored butterfly with various capabilities. Repetitive DNA sequence in MG's immunodominant MgPa operon has been considered as an efficient strategy to evade the host immune surveillance and mediate MG's genetic flexibility. Because of MG's pathogenicity in multiple organs, various antimicrobials are prescribed, further exerting selection pressure on microbes. Consequently, a rapidly increasing drug resistance in macrolide and moxifloxacin has been frequently reported globally, radically decreasing the overall cure rate of infection. Re-infection can be defined as a new MG infection through antigenic variation, while persistent infection refers to recurrent infections caused by the same MG isolate through acquisition of antimicrobial resistance. Therefore, we must differentiate between re-infection and persistent MG infection, and approach them accordingly. The genetic mechanisms of DNA variation in the MgPa operon and antibiotic resistance must be considered for the management of multicolored infection. In this respect, the unique genetic characteristics of MG will be described in detail. We hope that with this manuscript, clinicians can expand their understanding of recurrent MG infections and better choose an appropriate treatment for the infection in clinical setting.

Keyword

Mycoplasma genitalium; Genetics; Recurrence

MeSH Terms

Antigenic Variation
Base Sequence
Butterflies
DNA
Drug Resistance
Drug Resistance, Microbial
Genetic Variation*
Genetics
Genome
Hope
Mycoplasma genitalium*
Mycoplasma*
Operon
Pliability
Recurrence
Virulence
DNA

Figure

  • Fig 1. Phylogenetic tree of 16S rRNA gene sequences reveals that Mycoplasma pneumoniae M129 is closely related with Mycoplasma genitalium (MG). NR074611.1 is MG strain G37 (16S ribosomal RNA), NC000912.1 is M. pneumoniae M129 complete genome (16S ribosomal RNA), NC010503.1 is Ureaplasma parvum serotype 3 str. ATCC27815, complete genome (16S ribosomal RNA), NC011374 is Ureaplasma urealyticum serotype 10 str. ATCC33699, complete genome (16S ribosomal RNA), and AB680681.1 is Mycoplasma hominis gene for 16S ribosomal RNA, strain NBRC14850.

  • Fig. 2. Schematic view of Mycoplasma genitalium (MG). It appears as a flask or pear-shaped cell with a narrow terminal structure (A). This structure is crucial for MG to attach onto the host cell surfaces.

  • Fig. 3. Complete genome sequence in MgPa and MgPar genes of the Mycoplasma genitalium (MG) G37 strain. The expression sites for each of the three genes are present in only one copy; but there are nine repetitive elements in the form of truncated copies of MG191 and MG192 genes dispersed throughout the genome, designated as MgPa repeats or MgPar sequences [31,39,40].

  • Fig. 4. Twenty mgpB DNA sequences from the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/nuccore/) are evaluated for their homology using the Clustal W alignment algorithm (http://www.genome.jp/tools/clustalw/). Locations in the MG191 gene are indicated in the upper area. There are three areas of hot genetic variety in the mgpB gene (520-1,040 bp for B area, 2,340-2,990 bp for EF area, 3,250-3,640 bp for G area). The gray colors represent matching, while the black colors represent mismatching (http://multalin.toulouse.inra.fr/). MG: Mycoplasma genitalium.

  • Fig. 5. Sixty-four partial mgpC DNA sequences (Supplementary Table 2) from the National Center for Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih.gov/nuccore/) are collected and evaluated for their homology using the Clustal W alignment algorithm (http://www.genome.jp/tools/clustalw/). Locations in the mgpB gene are indicated in the upper area. The gray colors represent matching, while the black colors represent mismatching (http://multalin.toulouse.inra.fr).

  • Fig. 6. Twenty-four partial mgpC DNA sequences (Supplementary Table 3) from patient no. 126 are evaluated from the National Center for Biotechnology Information (NCBI) database (https://www.ncbi.nlm.nih.gov/nuccore/) to investigate the homology using the Clustal W alignment algorithm (http://www.genome.jp/ tools/clustalw/). Ma et al. [50] serially examined the DNA sequence changes in the mgpC gene in serial culturing periods (from the starting point to 4th subculturing period). The DNA sequences of MG192 changed rapidly in vitro within a short period of time. The gray colors represent matching, while the black colors represent mismatching (http://multalin.toulouse.inra.fr/multalin/multalin.html). MG: Mycoplasma genitalium.

  • Fig. 7. Phylogenetic analysis of the MG192 variable sequences from serially cultured in vitro samples from MG infected patients no. 61 and no. 126. Time intervals are described in Table 4. There are greater variations in the MG192 gene during sequential cultures, but the variances are more closely related within an individual patient than between the patients. MG: Mycoplasma genitalium.

  • Fig. 8. Ma et al. [51] intraurethrally inoculated a single cloned Mycoplasma genitalium (MG) strain G37 into one male chimpanzee's urethra. Urethral swabs were obtained at different time points (5 weeks, 9 weeks, and 11 weeks). Phylogenetic analysis in the MG192 gene revealed several MG192 sequences variants during an in vivo study.

  • Fig. 9. JX857899.1(61.0a) is the partial DNA sequences of MG192 gene at the starting point (11/20/2000) obtained from patient no. 61, as presented in Fig. 7. The JX857903.1(61.2e) is the partial DNA sequences of MG192 gene obtained from the same patient post 6 months (05/07/2001). EF117289.1 is the partial DNA sequences of MG strain G37 MgPar 8 region genomic sequence, FJ872575.1 is the partial DNA sequences of MG strain M2321 MgPar 2 region genomic sequence, and FJ872582.1 is the partial DNA sequences of MG strain M2321 MgPar 9 region genomic sequence. JX857903.1(61.2e) may get some AGT repeats in the original MG192 gene (JX857899.1), and newly mutated isolate (JX857903.1) is closely related to the partial DNA sequences of MG strain G37 MgPar 8 region genomic sequence (EF117289.1) (dotted box). MG: Mycoplasma genitalium.

  • Fig. 10. A schematic view of homologous recombination between MG192 and MgPar 8 in the MG type strain G37 during in vitro passage. A presents the alignment of a portion of the MG192 variable region and MgPar 8 in G37-P1, while B demonstrates the alignment of a portion of the recombined MG192 variable region and MgPar 8 in G37-P35, clearly depicting the sequence exchange at the recombination sites. Arrows indicate where sequence exchanges took place, with the reciprocal exchange (gene cross-over) shown by two arrows (area II) and gene conversion shown by one arrow (area I). MG: Mycoplasma genitalium.


Reference

1.Delva D. Social implications of sexually transmitted diseases. Can Fam Physician. 1983. 29:1933–6.
2.Anderson RM. Transmission dynamics of sexually transmitted infections. Holmes KK, Sparling PF, Mardh PA, Lemon SM, Stamm WE, Piot P, editors. editors.Sexually transmitted diseases. 3rd ed.New York: McGraw-Hill;1999. p. 25–37.
3.Takahashi S., Hamasuna R., Yasuda M., Ishikawa K., Hayami H., Uehara S, et al. Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan. J Infect Chemother. 2016. 22:581–6.
4.Krashin JW., Koumans EH., Bradshaw-Sydnor AC., Braxton JR., Evan Secor W., Sawyer MK, et al. Trichomonas vaginalis prevalence, incidence, risk factors and antibiotic-resistance in an adolescent population. Sex Transm Dis. 2010. 37:440–4.
Article
5.Papp JR., Abrams AJ., Nash E., Katz AR., Kirkcaldy RD., OʼConnor NP, et al. Azithromycin resistance and decreased ceftriaxone susceptibility in Neisseria gonorrhoeae, Hawaii, USA. Emerg Infect Dis. 2017. 23:830–2.
Article
6.Shipitsyna E., Rumyantseva T., Golparian D., Khayrullina G., Lagos AC., Edelstein I, et al. Prevalence of macrolide and fluoroquinolone resistance-mediating mutations in Mycoplasma genitalium in five cities in Russia and Estonia. PLoS One. 2017. 12:e0175763.
Article
7.Manhart LE., Jensen JS., Bradshaw CS., Golden MR., Martin DH. Efficacy of antimicrobial therapy for mycoplasma genitalium infections. Clin Infect Dis. 2015. 61(Suppl 8):S802–17.
8.Jensen JS., Bradshaw C. Management of Mycoplasma genitalium infections-can we hit a moving target? BMC Infect Dis. 2015. 15:343.
Article
9.Nijhuis RH., Severs TT., Van der Vegt DS., Van Zwet AA., Kusters JG. High levels of macrolide resistance-associated mutations in Mycoplasma genitalium warrant antibiotic susceptibility-guided treatment. J Antimicrob Chemother. 2015. 70:2515–8.
10.Salado-Rasmussen K., Jensen JS. Mycoplasma genitalium testing pattern and macrolide resistance: a Danish nationwide retrospective survey. Clin Infect Dis. 2014. 59:24–30.
Article
11.Horner P., Blee K., Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g! Curr Opin Infect Dis. 2014. 27:68–74.
12.Deguchi T., Kikuchi M., Yasuda M., Ito S. Multidrug-resistant Mycoplasma genitalium is increasing. Clin Infect Dis. 2016. 62:405–6.
13.Serra-Pladevall J., Barbera MJ., Rodriguez S., Bartolome-Comas R., Roig G., Juve R, et al. Neisseria gonorrhoeae antimicrobial susceptibility in Barcelona: penA, ponA, mtrR, and porB mutations and NG-MAST sequence types associated with decreased susceptibility to cephalosporins. Eur J Clin Microbiol Infect Dis. 2016. 35:1549–56.
Article
14.Hamasuna R. Mycoplasma genitalium in male urethritis: diagnosis and treatment in Japan. Int J Urol. 2013. 20:676–84.
15.Mondeja BA., Rodriguez NM., Barroto B., Blanco O., Jensen JS. Antimicrobial susceptibility patterns of recent Cuban Mycoplasma genitalium isolates determined by a modified cell-culture-based method. PLoS One. 2016. 11:e0162924.
Article
16.Dupin N., Bijaoui G., Schwarzinger M., Ernault P., Gerhardt P., Jdid R, et al. Detection and quantification of Mycoplasma genitalium in male patients with urethritis. Clin Infect Dis. 2003. 37:602–5.
Article
17.Falkow S., Isberg RR., Portnoy DA. The interaction of bacteria with mammalian cells. Annu Rev Cell Biol. 1992. 8:333–63.
Article
18.Olive AJ., Sassetti CM. Metabolic crosstalk between host and pathogen: sensing, adapting and competing. Nat Rev Microbiol. 2016. 14:221–34.
Article
19.Imming P., Sinning C., Meyer A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006. 5:821–34.
Article
20.Briken V. Molecular mechanisms of host-pathogen interactions and their potential for the discovery of new drug targets. Curr Drug Targets. 2008. 9:150–7.
Article
21.Munita JM., Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr. 2016. 4.
Article
22.Koike S., Yoshitani S., Kobayashi Y., Tanaka K. Phylogenetic analysis of fiber-associated rumen bacterial community and PCR detection of uncultured bacteria. FEMS Microbiol Lett. 2003. 229:23–30.
Article
23.Riley DE., Berger RE., Miner DC., Krieger JN. Diverse and related 16S rRNA-encoding DNA sequences in prostate tissues of men with chronic prostatitis. J Clin Microbiol. 1998. 36:1646–52.
Article
24.Garza-Ramos G., Xiong L., Zhong P., Mankin A. Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA. J Bacteriol. 2001. 183:6898–907.
Article
25.Drlica K., Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev. 1997. 61:377–92.
Article
26.Blango MG., Mulvey MA. Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob Agents Chemother. 2010. 54:1855–63.
27.Lee G., Romih R., Zupancic D. Cystitis: from urothelial cell biology to clinical applications. Biomed Res Int. 2014. DOI: doi: 10.1155/2014/473536.
Article
28.NCBI. Taxonomy [Internet]. Bethesda: NCBI;2017. [cited 2017 Jun 10]. Available from:. https://www.ncbi.nlm.nih.gov/Taxonomy.
29.Taylor-Robinson D., Furr PM. Failure of Mycoplasma pneumoniae infection to confer protection against Mycoplasma genitalium: observations from a mouse model. J Med Microbiol. 2001. 50:383–4.
Article
30.Wang RY., Grandinetti T., Shih JW., Weiss SH., Haley CL., Hayes MM, et al. Mycoplasma genitalium infection and host antibody immune response in patients infected by HIV, patients attending STD clinics and in healthy blood donors. FEMS Immunol Med Microbiol. 1997. 19:237–45.
Article
31.Fraser CM., Gocayne JD., White O., Adams MD., Clayton RA., Fleischmann RD, et al. The minimal gene complement of Mycoplasma genitalium. Science. 1995. 270:397–403.
32.Razin S., Yogev D., Naot Y. Molecular biology and pathogenicity of mycoplasmas. Microbiol Mol Biol Rev. 1998. 62:1094–156.
Article
33.Ma L., Jensen JS., Myers L., Burnett J., Welch M., Jia Q, et al. Mycoplasma genitalium: an efficient strategy to generate genetic variation from a minimal genome. Mol Microbiol. 2007. 66:220–36.
Article
34.Rottem S. Interaction of mycoplasmas with host cells. Physiol Rev. 2003. 83:417–32.
Article
35.Reinton N., Moi H., Olsen AO., Zarabyan N., Bjerner J., Tønseth TM, et al. Anatomic distribution of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium infections in men who have sex with men. Sex Health. 2013. 10:199–203.
Article
36.Baseman JB., Dallo SF., Tully JG., Rose DL. Isolation and characterization of Mycoplasma genitalium strains from the human respiratory tract. J Clin Microbiol. 1988. 26:2266–9.
Article
37.Taylor-Robinson D., Jensen JS. Mycoplasma genitalium: from Chrysalis to multicolored butterfly. Clin Microbiol Rev. 2011. 24:498–514.
Article
38.Mernaugh GR., Dallo SF., Holt SC., Baseman JB. Properties of adhering and nonadhering populations of Mycoplasma genitalium. Clin Infect Dis. 1993. 17(Suppl 1):S69–78.
Article
39.Ma L., Jensen JS., Mancuso M., Hamasuna R., Jia Q., McGowin CL, et al. Variability of trinucleotide tandem repeats in the MgPa operon and its repetitive chromosomal elements in Mycoplasma genitalium. J Med Microbiol. 2012. 61:191–7.
Article
40.Ma L., Jensen JS., Mancuso M., Hamasuna R., Jia Q., McGowin CL, et al. Genetic variation in the complete MgPa operon and its repetitive chromosomal elements in clinical strains of Mycoplasma genitalium. PLoS One. 2010. 5:e15660.
Article
41.Iverson-Cabral SL., Astete SG., Cohen CR., Rocha EP., Totten PA. Intrastrain heterogeneity of the mgpB gene in Mycoplasma genitalium is extensive in vitro and in vivo and suggests that variation is generated via recombination with repetitive chromosomal sequences. Infect Immun. 2006. 74:3715–26.
42.Dallo SF., Baseman JB. Adhesin gene of Mycoplasma genitalium exists as multiple copies. Microb Pathog. 1991. 10:475–80.
Article
43.Hu PC., Schaper U., Collier AM., Clyde WA Jr., Horikawa M., Huang YS, et al. A Mycoplasma genitalium protein resembling the Mycoplasma pneumoniae attachment protein. Infect Immun. 1987. 55:1126–31.
Article
44.Clyde WA Jr., Hu PC. Antigenic determinants of the attachment protein of Mycoplasma pneumoniae shared by other pathogenic Mycoplasma species. Infect Immun. 1986. 51:690–2.
Article
45.Burgos R., Pich OQ., Ferrer-Navarro M., Baseman JB., Querol E., Pinol J. Mycoplasma genitalium P140 and P110 cytadhesins are reciprocally stabilized and required for cell adhesion and terminal-organelle development. J Bacteriol. 2006. 188:8627–37.
46.Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006. 124:783–801.
Article
47.Schmid-Hempel P. Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomenaʼ such as virulence. Philos Trans R Soc Lond B Biol Sci. 2009. 364:85–98.
Article
48.Hornef MW., Wick MJ., Rhen M., Normark S. Bacterial strategies for overcoming host innate and adaptive immune responses. Nat Immunol. 2002. 3:1033–40.
Article
49.NCBI. Nucleotide [Internet]. Bethesda: NCBI;2017. [cited 2017 Jun 10]. Available from:. https://www.ncbi.nlm.nih.gov/nuccore/.
50.Ma L., Mancuso M., Williams JA., Van Der Pol B., Fortenberry JD., Jia Q, et al. Extensive variation and rapid shift of the MG192 sequence in Mycoplasma genitalium strains from patients with chronic infection. Infect Immun. 2014. 82:1326–34.
Article
51.Ma L., Jensen JS., Mancuso M., Myers L., Martin DH. Kinetics of genetic variation of the Mycoplasma genitalium MG192 gene in experimentally infected chimpanzees. Infect Immun. 2015. 84:747–53.
Article
52.Taylor-Robinson D. The Harrison lecture. The history and role of Mycoplasma genitalium in sexually transmitted diseases. Genitourin Med. 1995. 71:1–8.
Article
53.Jensen JS. Mycoplasma genitalium: the aetiological agent of urethritis and other sexually transmitted diseases. J Eur Acad Dermatol Venereol. 2004. 18:1–11.
Article
54.Jensen JS., Cusini M., Gomberg M., Moi H. 2016 European guideline on Mycoplasma genitalium infections. J Eur Acad Dermatol Venereol. 2016. 30:1650–6.
Article
55.Deguchi T., Ito S., Yasuda M., Kondo H., Yamada Y., Nakane K, et al. Emergence of Mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in GyrA and ParC in Japan. J Infect Chemother. 2017. 23:648–50.
Article
56.Braam JF., van Dommelen L., Henquet CJ., van de Bovenkamp JH., Kusters JG. Multidrug-resistant Mycoplasma genitalium infections in Europe. Eur J Clin Microbiol Infect Dis. 2017 Mar 30. [Epub].DOI: doi: 10.1007/s10096-017-2969-9.
Article
57.Murray GL., Bradshaw CS., Bissessor M., Danielewski J., Garland SM., Jensen JS, et al. Increasing macrolide and fluoroquinolone resistance in mycoplasma genitalium. Emerg Infect Dis. 2017. 23:809–12.
Article
58.Hamasuna R., Osada Y., Jensen JS. Isolation of Mycoplasma genitalium from first-void urine specimens by coculture with Vero cells. J Clin Microbiol. 2007. 45:847–50.
59.Bocchetta M., Xiong L., Mankin AS. 23S rRNA positions essential for tRNA binding in ribosomal functional sites. Proc Natl Acad Sci U S A. 1998. 95:3525–30.
Article
60.Beringer M., Rodnina MV. Importance of tRNA interactions with 23S rRNA for peptide bond formation on the ribosome: studies with substrate analogs. Biol Chem. 2007. 388:687–91.
Article
61.Brosius J., Dull TJ., Noller HF. Complete nucleotide sequence of a 23S ribosomal RNA gene from Escherichia coli. Proc Natl Acad Sci U S A. 1980. 77:201–4.
Article
62.Harrod R., Lovett PS. Peptide inhibitors of peptidyltransferase alter the conformation of domains IV and V of large subunit rRNA: a model for nascent peptide control of translation. Proc Natl Acad Sci U S A. 1995. 92:8650–4.
Article
63.Schlunzen F., Zarivach R., Harms J., Bashan A., Tocilj A., Albrecht R, et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001. 413:814–21.
Article
64.Hansen JL., Ippolito JA., Ban N., Nissen P., Moore PB., Steitz TA. The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol Cell. 2002. 10:117–28.
Article
65.Kim JH., Kim JY., Yoo CH., Seo WH., Yoo Y., Song DJ, et al. Macrolide resistance and its impacts on M. Pneumoniae pneumonia in children: comparison of two recent epidemics in Korea. Allergy Asthma Immunol Res. 2017. 9:340–6.
Article
66.Anagrius C., Lore B., Jensen JS. Treatment of Mycoplasma genitalium. Observations from a Swedish STD clinic. PLoS One. 2013. 8:e61481.
Article
67.Couldwell DL., Lewis DA. Mycoplasma genitalium infection: current treatment options, therapeutic failure, and resistance-associated mutations. Infect Drug Resist. 2015. 8:147–61.
68.Couldwell DL., Tagg KA., Jeoffreys NJ., Gilbert GL. Failure of moxifloxacin treatment in Mycoplasma genitalium infections due to macrolide and fluoroquinolone resistance. Int J STD AIDS. 2013. 24:822–8.
Article
69.Kikuchi M., Ito S., Yasuda M., Tsuchiya T., Hatazaki K., Takanashi M, et al. Remarkable increase in fluoroquinolone-resistant Mycoplasma genitalium in Japan. J Antimicrob Chemother. 2014. 69:2376–82.
Article
70.Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002. 3:430–40.
Article
71.Takahashi S., Hamasuna R., Yasuda M., Ito S., Ito K., Kawai S, et al. Clinical efficacy of sitafloxacin 100 mg twice daily for 7 days for patients with non-gonococcal urethritis. J Infect Chemother. 2013. 19:941–5.
72.Hooper DC. Mode of action of fluoroquinolones. Drugs. 1999. 58(Suppl 2):6–10.
Article
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