Invertible Promoters Mediate Bacterial Phase Variation, Antibiotic Resistance, and Host Adaptation in the Gut

Overview

Journal Science

Specialty Science

Date 2019 Jan 12

PMID 30630933

Citations 66

Authors

Xiaofang Jiang

A Brantley Hall

Timothy D Arthur

Damian R Plichta

Christian T Covington

Mathilde Poyet

Jessica Crothers

Peter L Moses

Andrew C Tolonen

Hera Vlamakis

Eric J Alm

Ramnik J Xavier

Affiliations

Soon will be listed here.

Abstract

Phase variation, the reversible alternation between genetic states, enables infection by pathogens and colonization by commensals. However, the diversity of phase variation remains underexplored. We developed the PhaseFinder algorithm to quantify DNA inversion-mediated phase variation. A systematic search of 54,875 bacterial genomes identified 4686 intergenic invertible DNA regions (invertons), revealing an enrichment in host-associated bacteria. Invertons containing promoters often regulate extracellular products, underscoring the importance of surface diversity for gut colonization. We found invertons containing promoters regulating antibiotic resistance genes that shift to the ON orientation after antibiotic treatment in human metagenomic data and in vitro, thereby mitigating the cost of antibiotic resistance. We observed that the orientations of some invertons diverge after fecal microbiota transplant, potentially as a result of individual-specific selective forces.

Citing Articles

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References

Henderson I, Owen P, Nataro J . Molecular switches--the ON and OFF of bacterial phase variation. Mol Microbiol. 1999; 33(5):919-32. DOI: 10.1046/j.1365-2958.1999.01555.x. View

Rice P, Longden I, Bleasby A . EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet. 2000; 16(6):276-7. DOI: 10.1016/s0168-9525(00)02024-2. View

Bayley D, Rocha E, Smith C . Analysis of cepA and other Bacteroides fragilis genes reveals a unique promoter structure. FEMS Microbiol Lett. 2000; 193(1):149-54. DOI: 10.1111/j.1574-6968.2000.tb09417.x. View

Ermolaeva M, White O, Salzberg S . Prediction of operons in microbial genomes. Nucleic Acids Res. 2001; 29(5):1216-21. PMC: 29727. DOI: 10.1093/nar/29.5.1216. View

Horino A, Sasaki Y, Sasaki T, Kenri T . Multiple promoter inversions generate surface antigenic variation in Mycoplasma penetrans. J Bacteriol. 2002; 185(1):231-42. PMC: 141813. DOI: 10.1128/JB.185.1.231-242.2003. View

Coyne M, Weinacht K, Krinos C, Comstock L . Mpi recombinase globally modulates the surface architecture of a human commensal bacterium. Proc Natl Acad Sci U S A. 2003; 100(18):10446-51. PMC: 193581. DOI: 10.1073/pnas.1832655100. View

Beissbarth T, Speed T . GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics. 2004; 20(9):1464-5. DOI: 10.1093/bioinformatics/bth088. View

Hinde P, Deighan P, Dorman C . Characterization of the detachable Rho-dependent transcription terminator of the fimE gene in Escherichia coli K-12. J Bacteriol. 2005; 187(24):8256-66. PMC: 1317003. DOI: 10.1128/JB.187.24.8256-8266.2005. View

Siguier P, Perochon J, Lestrade L, Mahillon J, Chandler M . ISfinder: the reference centre for bacterial insertion sequences. Nucleic Acids Res. 2005; 34(Database issue):D32-6. PMC: 1347377. DOI: 10.1093/nar/gkj014. View

10.

Kawula T, Orndorff P . Rapid site-specific DNA inversion in Escherichia coli mutants lacking the histonelike protein H-NS. J Bacteriol. 1991; 173(13):4116-23. PMC: 208061. DOI: 10.1128/jb.173.13.4116-4123.1991. View

11.

Wagner A, Lewis C, Bichsel M . A survey of bacterial insertion sequences using IScan. Nucleic Acids Res. 2007; 35(16):5284-93. PMC: 2018620. DOI: 10.1093/nar/gkm597. View

12.

Coyne M, Comstock L . Niche-specific features of the intestinal bacteroidales. J Bacteriol. 2007; 190(2):736-42. PMC: 2223690. DOI: 10.1128/JB.01559-07. View

13.

Molina N, van Nimwegen E . Universal patterns of purifying selection at noncoding positions in bacteria. Genome Res. 2007; 18(1):148-60. PMC: 2134783. DOI: 10.1101/gr.6759507. View

14.

Holden N, Blomfield I, Uhlin B, Totsika M, Kulasekara D, Gally D . Comparative analysis of FimB and FimE recombinase activity. Microbiology (Reading). 2007; 153(Pt 12):4138-4149. DOI: 10.1099/mic.0.2007/010363-0. View

15.

Liu C, Lee S, VanLare J, Kasper D, Mazmanian S . Regulation of surface architecture by symbiotic bacteria mediates host colonization. Proc Natl Acad Sci U S A. 2008; 105(10):3951-6. PMC: 2268772. DOI: 10.1073/pnas.0709266105. View

16.

Coyne M, Chatzidaki-Livanis M, Paoletti L, Comstock L . Role of glycan synthesis in colonization of the mammalian gut by the bacterial symbiont Bacteroides fragilis. Proc Natl Acad Sci U S A. 2008; 105(35):13099-104. PMC: 2529095. DOI: 10.1073/pnas.0804220105. View

17.

Bayliss C . Determinants of phase variation rate and the fitness implications of differing rates for bacterial pathogens and commensals. FEMS Microbiol Rev. 2009; 33(3):504-20. DOI: 10.1111/j.1574-6976.2009.00162.x. View

18.

Bailey T, Boden M, Buske F, Frith M, Grant C, Clementi L . MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009; 37(Web Server issue):W202-8. PMC: 2703892. DOI: 10.1093/nar/gkp335. View

19.

Nakayama-Imaohji H, Hirakawa H, Ichimura M, Wakimoto S, Kuhara S, Hayashi T . Identification of the site-specific DNA invertase responsible for the phase variation of SusC/SusD family outer membrane proteins in Bacteroides fragilis. J Bacteriol. 2009; 191(19):6003-11. PMC: 2747901. DOI: 10.1128/JB.00687-09. View

20.

Czurda S, Jechlinger W, Rosengarten R, Chopra-Dewasthaly R . Xer1-mediated site-specific DNA inversions and excisions in Mycoplasma agalactiae. J Bacteriol. 2010; 192(17):4462-73. PMC: 2937384. DOI: 10.1128/JB.01537-09. View