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Phase and Antigenic Variation in Bacteria Marjan W CLINICAL MICROBIOLOGY REVIEWS, July 2004, p. 581–611 Vol. 17, No. 3 0893-8512/04/$08.00ϩ0 DOI: 10.1128/CMR.17.3.581–611.2004 Copyright © 2004, American Society for Microbiology. All Rights Reserved. Phase and Antigenic Variation in Bacteria Marjan W. van der Woude1* and Andreas J. Ba¨umler2 Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-60761 and Department of Medical Microbiology and Immunology, College of Medicine, TexasA&MUniversity System Health Science Center, College Station, Texas 77843-11142 INTRODUCTION .......................................................................................................................................................581 PHASE-VARIABLE PHENOTYPES AND MOIETIES .........................................................................................582 Colony Morphology and Opacity..........................................................................................................................582 Capsule.....................................................................................................................................................................583 Downloaded from Fimbriae and Pili....................................................................................................................................................584 Flagella .....................................................................................................................................................................584 Other Surface-Exposed Proteins...........................................................................................................................584 LPS and LOS Modification: Variation in Expression of Surface Epitopes ...................................................585 DNA Restriction-Modification Systems ...............................................................................................................586 Regulatory Proteins ................................................................................................................................................586 Metabolism-Associated Genes...............................................................................................................................586 Phage Genes ............................................................................................................................................................587 Concluding Remarks ..............................................................................................................................................587 MOLECULAR MECHANISMS OF PHASE VARIATION...................................................................................587 http://cmr.asm.org/ Genetic Regulation..................................................................................................................................................587 Short sequence repeats and slipped-strand mispairing ................................................................................587 Homologous (general) recombination..............................................................................................................589 Site-specific recombination................................................................................................................................591 (i) Inversion of a DNA element by CSSR ...................................................................................................591 (ii) Insertion and excision of genetic elements from the chromosome ...................................................593 Epigenetic Regulation.............................................................................................................................................594 PAP phase variation...........................................................................................................................................594 Ag43 phase variation..........................................................................................................................................595 Phase Variation as Part of the Cell’s Regulatory Network ..............................................................................596 on September 12, 2018 by guest Cross regulation..................................................................................................................................................596 Environmental regulation..................................................................................................................................596 Concluding Remarks ..............................................................................................................................................597 GENOMICS AND PHASE VARIATION.................................................................................................................597 BIOLOGICAL SIGNIFICANCE OF PHASE VARIATION..................................................................................598 Persistence through Surface Variation ................................................................................................................598 Evasion of Cross-Immunity...................................................................................................................................600 DNA Restriction-Modification Systems ...............................................................................................................601 DIAGNOSTIC AND EXPERIMENTAL SIGNIFICANCE OF PHASE VARIATION .......................................601 ACKNOWLEDGMENTS ...........................................................................................................................................602 REFERENCES ............................................................................................................................................................602 INTRODUCTION (on/off) expressing phase, resulting in variation in the level of expression of one or more proteins between individual cells of Phenotypic variation in bacteria has long been recognized a clonal population. What distinguishes this variation from and has been a focus of study mainly in bacterial pathogens. genetic noise and classical gene regulation is that there is a This interest has been fueled by the observation that pheno- genetic or epigenetic mechanism that allows the variability to typic variation in pathogens, most readily visible as colony be heritable. This means that a daughter cell will inherit the variation, is often associated with the virulence of the strain. expression phase of the parent. However, the phase of expres- Alternating between two phenotypes in a heritable and revers- ible manner can be classified as phase variation or antigenic sion must also be reversible between generations, and the variation. These terms, phase variation and antigenic variation, frequency of this reversion should exceed that of a random however, have been used in various ways. Phase variation in mutation. Thus, in a clonal population after cell division, the general refers to a reversible switch between an “all-or-none” majority of daughter cells will retain the expression phase of the parent but a minority will have switched expression phase. The switch is a stochastic event, even though the chance that it occurs in some cases can be influenced by external factors; in * Corresponding author. Mailing address: Department of Microbi- other words, the switching frequency can be modulated. The ology, University of Pennsylvania, 202A Johnson Pavilion, 3610 Ham- ilton Walk, Philadelphia, PA 19104-6076. Phone: (215) 573-4104. Fax: frequency with which this occurs is characteristic for the gene, (215) 573-4184. E-mail [email protected]. the bacterial species, and the regulatory mechanism. This can 581 582 VAN DER WOUDE AND BA¨ UMLER CLIN.MICROBIOL.REV. be as high as a change in 1 cell per 10 per generation but more are provided for systems that are not described in detail but often is on the order of 1 change per 103 cells per generation. may be of interest to the reader, and, where relevant, we refer The term “phase variation” is used in other contexts as well, the reader to Table 1 or other sections of this review where describing phenotypic “phase variants” of a species in which additional aspects of the system are discussed. the change is irreversible or variants that are a result of envi- ronmental regulation, selection, or unidirectional mutation. In Colony Morphology and Opacity this review, however, we adhere to the definition in the sense that the expression phase must be inherited by a genetic of Historically, phase-variable structures have been recognized epigenetic mechanism and that this change must be reversible. by their effect on colony morphology that led to descriptions The actual switching frequencies are not reported here, be- like dry versus moist, ruffled versus smooth, and opaque versus cause the methods that are used to determine them vary sig- translucent. These changes in colony morphology can be at- nificantly and because they can be modulated by growth con- tributed to phase variation of a variety of surface-exposed ditions. Differences are therefore difficult to interpret. proteins, of the capsule, and of cell wall composition. These Downloaded from Antigenic variation refers to the expression of functionally changes most probably lead to altered packing of cells in the conserved moieties within a clonal
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