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PubMed2025

Quorum sensing and DNA methylation play active roles in clinical Burkholderia phase variation.

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions, exemplified by variable colony morphotypes. In Burkholderia pseudomallei, discrete genomic alterations and modulation of gene expression facilitate adaptation. Adapted variants of species within the Burkholderia cepacia complex (Bcc) often lose the pC3 virulence megaplasmid, impacting their colony morphology and their production of virulence factors. In this study, we characterize variants arising in Burkholderia ambifaria clinical isolates using proteomics and phenotypic tests and show that some of them have retained the pC3, indicating a distinct phase variation mechanism at play in this Bcc species. Interestingly, variants of B. ambifaria strains CEP0996 (pC3-null) and HSJ1 (pC3-positive) still share similarities in phenotypes controlled by the Cep quorum-sensing (QS) system. We further investigated the role of QS in B. ambifaria HSJ1 phase variation and confirmed that the Cep QS system is important for the emergence of variants. Given that DNA methylation is a key epigenetic factor regulating virulence factors in Burkholderia cenocepacia, we hypothesized that adenosine DNA methylation also governs phase variation in B. ambifaria HSJ1. By deleting the genes encoding putative adenosine DNA methyltransferases, we discovered that an orphan type II DNA methyltransferase inhibits the emergence of phase variants. This study is the first to demonstrate that quorum sensing and adenosine DNA methylation are two antagonistic systems independently controlling phase variation in B. ambifaria.IMPORTANCESome Burkholderia species are pathogenic to plants, animals, or humans. In immunocompromised individuals, and people suffering from cystic fibrosis, infection from the Burkholderia cepacia complex (Bcc) can lead to "cepacia syndrome." In northern Australia and southeast Asia, melioidosis caused by Burkholderia pseudomallei is prevalent among native population, particularly among people with diabetes, chronic lung or kidney disease or alcoholism. Burkholderia's phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing its survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group and is the first to report that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying mechanisms of CMV could lead to the development of targeted therapies against these highly antibiotic-tolerant bacteria.

Quorum Sensing↗
PubMed1978

[Antibody induced phase variation in Pseudomonas aeruginosa (author's transl)].

To extend the flagella specific H antigenic schema of P. aeruginosa (ANSORG, 1978), investigations are carried out to reveal phase variation in this species as in Salmonella or Arizona. With conventional methods, i.e. examination of single colonies after plating the cultures on standard nutrient agar or the phase reversal techniques of Craigie (1931) and Gard (1938) by adding homologous anti-OH-serum of different amounts in semisolid agar medium, no change of the flagellar antigens of various P. aeruginosa strains is observed using the indirect fluorescent antibody technique. When subcultivated in pure homologous anti-OH-serum, however, the cells express stepwise a second H phase, which is different from the original flagellar antigens. In control experiments with serum from non-immunized rabbits the original flagellar antigens remain constant. The phase variation affects only the H antigen, is reversible by cultivation on soft agar medium and is characterized by the nonspecific type-overlapping antigen u. After absorption of immunserum prepared with cells cultivated in homologous anti-OH-serum by cells cultivated on soft agar medium, an antiserum specific for factor u is obtained. Since fresh isolates do not react with anti-u-serum, the diphasic nature of P. aeruginosa is probably of minor significance for H typing in practice.

Antigens, Bacterial↗
PubMed2025

100+ years of phase variation: the premier bacterial bet-hedging phenomenon.

Stochastic, reversible switches in the expression of Salmonella flagella variants were first described by Andrewes in 1922. Termed phase variation (PV), subsequent research found that this phenomenon was widespread among bacterial species and controlled expression of major determinants of bacterial-host interactions. Underlying mechanisms were not discovered until the 1970s/1980s but were found to encompass intrinsic aspects of DNA processes (i.e. DNA slippage and recombination) and DNA modifications (i.e. DNA methylation). Despite this long history, discoveries are ongoing with expansions of the phase-variable repertoire into new organisms and novel insights into the functions of known loci and switching mechanisms. Some of these discoveries are somewhat controversial as the term 'PV' is being applied without addressing key aspects of the phenomenon such as whether mutations or epigenetic changes are reversible and generated prior to selection. Another 'missing' aspect of PV research is the impact of these adaptive switches in real-world situations. This review provides a perspective on the historical timeline of the discovery of PV, the current state-of-the-art, controversial aspects of classifying phase-variable loci and possible 'missing' real-world effects of this phenomenon.

Gene Expression Regulation, Bacterial↗
PubMed1979

Phase variation in Salmonella: genetic analysis of a recombinational switch.

The alternative expression of Salmonella genes H1 and H2, which specify different flagellar antigens, results in the oscillation of phenotype known as phase variation. This alternation is controlled by the inversion of an 800-base-pair sequence of DNA adjacent to, or including part of, the H2 gene. The invertable region was presumed to regulate the function of a promoter and to include specific sites at which a recombinational event, resulting in the inversion, could occur. Here we report genetic manipulations of hybrid lambda phage carrying the H2 gene that were used to define the H2 promoter region and the recombinational sites. The H2 gene fragment was inserted on a hybrid lambda phage next to the cheW gene, which lacked a promoter element. In the resulting fusion, cheW gene activity was restored, the expression of the H2 and cheW genes was controlled coordinately by the inversion, and the polarity of transcription and location of the H2 gene could be determined. Evidence from this type of gene fusion suggested that the H2 gene promoter is included in the inversion region. Hybrid H2 phage were constructed that contained substitutions for regions of the H2 gene. In contrast to hybrid lambda containing the H2 gene, which alternate between "on" and "off" states, several substituted lambdaH2 were fixed in the "on" state. A site necessary for the recombinational event must have been removed in these fixed lambdaH2.

Bacterial Proteins↗
PubMed1977

Analysis of the phase variation in lambda reduced immunity lysogens.

Two distinct phases characterized by different levels of immunity that appear in some E. coli strains lysogenic for reduced immunity mutants of bacteriophage lambda are identified as single and tandem double lysogens respectively on the basis of DNA-DNA hybridization experiments and the requirement of the phage xis function for the transition from a single to a double, and of the host recA function for the transition from a double to a single lysogen (in a xis- condition). Rim lysogens with a further increase in immunity, containing some 5 copies of the lambda genome per host genome, have also been observed. It is argued that the different levels of immunity are a direct reflection of the CI gene dosage effect. An unexplained finding is that rim single lysogens yield double lysogens with a frequency of near 1% per generation, whereas cured cells fail to appear even at a frequency 100 times lower.

Cell Division↗
PubMed1979

Flagellar-phase variation: isolation of the rh1 gene.

In Salmonella, expression of flagellar antigen alternates between two serotypes (phases) encoded by two genes, H1 and H2. The mechanism which controls the alternative expression of the H1 and H2 genes was examined by cloning these genes and the genetic elements which control their activity on hybrid vehicles in Escherichia coli. H2 gene activity was shown to be controlled by a recombinational switch located adjacent to the H2 gene. Activity of the H1 gene is thought to be repressed, when the H2 gene is expressed, by the product of another gene, rh1 (repressor of H1), which is controlled coordinately with the H2 gene. In this report, we describe the construction of hybrid lambda vehicles which contain, in addition to the H2 gene, a genetic activity corresponding to rh1. Variation of flagellar antigens analogous to that observed in Salmonella was observed when E. Coli strains were transduced with the hybrid lambda. By using the lambdaH2rh1 hybrid to program protein synthesis in UV-irradiated cells, the synthesis of a polypeptide was correlated with rh1 gene product activity. We conclude that the H2 region consists of two cotranscribed genes, H2 and rh1. The expression of both gene products is regulated by the same recombinational event.

Bacterial Proteins↗
PubMed1977

Ultrastructural investigations on surface structures involved in Coxiella burnetii phase variation.

By using the cytochemical staining procedure with concanavalin A, horseradish peroxidase, and diaminobenzidine, no surface carbohydrates with terminal alpha-glucosyl or sterically closely related residues could be detected on the cell walls of Coxiella burnetii phases I and II. Using a polycationized ferritin derivative as a cytochemical probe, anionic binding sites were visualized in the electron microscope on cell membranes of C. burnetii phase II, but not on phase I organisms. The sites appeared to be masked in phase I particles. Anionic sites could be demonstrated on phase I organisms after treatment with NaIO4 or dimethyl sulfoxide. A number of different biological properties of C. burnetii phases I and II may depend on the presence or absence of a net negative charge on the surface of the cell walls of these organisms.

Acetone↗
PubMed1975

Integration, at hag or elsewhere, of H2 (phase-2 flagellin) genes transduced from Salmonella to Escherichia coli.

A fla mutant of E. coli K12 was given fla+ and H1-i by phage P1kc cotransduction from S. typhimurium, then made Fla- by transduction of ah1 from S. typhimurium. Motile clones expressing a Salmonella phase-2 antigen, e,n,x or 1,2, were obtained from the K12 i ah1 (therefore Fla-) line by P1kc transduction of flagellin-specifying genes, H2-e,n,x or H2-1,2, from Salmonella donors. Of eighteen such transductants sixteen failed to show phase variation, and on transduction back to Salmonella each structural gene for a phase-2 flagellin (or at least for its antigenically determinant part) now behaved as an allele of H1, presumably in consequence of incorporation in the hag region of the K12 recipient, in place of H1-i ah1. The e,n,x- and 1,2-specifying genes were shown to have been integrated in the K12 chromosome without the linked H1-repressor gene or the adjacent vh2 gene (controlling rate of phase-variation) and they responded to the repressing activity of an H2 allele elsewhere in the cell, in this respect resembling H1 alleles of Salmonella or hag alleles of E. coli. Two K12 e,n,x transductants had flagellin-specifying genes which when transduced back to Salmonella were integrated at H2; they are inferred to have resulted from integration of H2-e,n,x in the K12 chromosome elsewhere than the hag region. These two clones showed phase variation, between a Fla+ phase, with antigen e,n,x, and a Fla- phase (with e,n,x determinant in the nonactive state and the determinant of antigen i inactivated by ah1). The two integrated e,n,x genes when in the "active" state retained the ability to repress expression of exogenote H1 alleles, which indicates that the closely linked H1-repressor gene also was integrated. One of the two exceptional transductants derived its e,n,x gene from a Salmonella donor with the linked vh2- gene, which in Salmonella almost entirely prevents change of phase, and transduction of this e,n,x gene back to Salmonella recipients proved that vh2- had been incorporated into the E. coli chromosome along with the e,n,x determinant and the H1-repressor gene. The high frequency of change of phase (Fla+ in equilibrium Fla-) in the K12 e,n,x vh2- transductant concerned suggests that vh2- fails to prevent frequent change of state of the phase-determined part of H2 when vh2- and H2 are incorporated in the E. coli chromosome.

Bacterial Proteins↗
PubMed2005

Strain-specific differences in Neisseria gonorrhoeae associated with the phase variable gene repertoire.

BACKGROUND: There are several differences associated with the behaviour of the four main experimental Neisseria gonorrhoeae strains, FA1090, FA19, MS11, and F62. Although there is data concerning the gene complements of these strains, the reasons for the behavioural differences are currently unknown. Phase variation is a mechanism that occurs commonly within the Neisseria spp. and leads to switching of genes ON and OFF. This mechanism may provide a means for strains to express different combinations of genes, and differences in the strain-specific repertoire of phase variable genes may underlie the strain differences. RESULTS: By genome comparison of the four publicly available neisserial genomes a revised list of 64 genes was created that have the potential to be phase variable in N. gonorrhoeae, excluding the opa and pilC genes. Amplification and sequencing of the repeat-containing regions of these genes allowed determination of the presence of the potentially unstable repeats and the ON/OFF expression state of these genes. 35 of the 64 genes show differences in the composition or length of the repeats, of which 28 are likely to be associated with phase variation. Two genes were expressed differentially between strains causing disseminated infection and uncomplicated gonorrhoea. Further study of one of these in a range of clinical isolates showed this association to be due to sample size and is not maintained in a larger sample. CONCLUSION: The results provide us with more evidence as to which genes identified through comparative genomics are indeed phase variable. The study indicates that there are large differences between these four N. gonorrhoeae strains in terms of gene expression during in vitro growth. It does not, however, identify any clear patterns by which previously reported behavioural differences can be correlated with the phase variable gene repertoire.

Bacterial Proteins↗
PubMed1977

Bacteriological variation among Bordetella bronchiseptica isolates from dogs and other species.

Bacteriological properties of 50 isolates of Bordetella bronchiseptica were compared. Phase variation, which involved colonial morphology and its associated characters of hemagglutination, hemolysis, acriflavine agglutination; crystal violet staining, flagellation, and fimbriation, occurred among these isolates. Organisms representing the three observed morphotypes did not have different growth rates, nor were any differences in their bacteriological characteristics observed after repeated subculture on agar. There were also variations in antimicrobial drug susceptibility, especially to sulfonamide-trimethoprim, and in nitrate reduction. The relationships among these variable parameters were not apparent. None of the observed variations could be attributed to differences in the species of origin.

Animals↗
PubMed1977

Prolactin and murine mammary tumorigenesis: a review.

It is unequivocal that prolactin is an influential hormone in murine mammary tumorigenesis. The Berenblum hypothesis (7), a well-known theoretical model of tumorigenesis that depicts this oncogenic process as a two-step mechanism, i.e., initiation and promotion, is a conceptual scheme in which the action of prolactin in mammary tumorigenesis may be understood. According to this conceptual model, prolactin would participate in both the initiation and promotion steps of mammary tumorigenesis, In the initiation phase, variations in prolactin secretion appear to influence the metabolism of the mammary epithelium, so that the epithelium would be either more receptive to or refractory to an initiating agent (e.g., chemical carcinogen, physical carcinogens, oncogenic viruses, ets.) i.e., a permissive action. In the promotion phase, prolactin may act as either a promoter or an antipromoter of the "transformed" mammary epithelium. In promotion, the hormone may either directly or indirectly (via the ovary) stimulate mitotic activity of the "transformed" epithelium. In antipromotion the hormone, in the presence of requisite hormones (e.g., glucocorticoids), may synergistically induce differentiation (e.g., lactation) in the "transformed" epithelium. A tumor would result in the former (promotion) but not in the latter (antipromotion) case. Whether or not prolactin is significantly influential in human breast tumorigenesis remains to be determined. This is an extremely important area of research which is justifiably receiving increased attention. For if prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated prolactin suppression.

Adrenal Glands↗
PubMed1978

RF magnetic field penetration, phase shift and power dissipation in biological tissue: implications for NMR imaging.

The magnetic field penetration, phase shift and power deposition in planar and cylindrical models of biological tissue exposed to a sinusoidal time-dependent magnetic field have been investigated theoretically over the frequency range 1 to 100 MHz. The results are based on measurements of the relative permittivity and resistivity dispersions of a variety of freshly excised rat tissue at 37 and 25 degrees C, and are analysed in terms of their implications for human body nuclear magnetic resonance (NMR) imaging. The results indicate that at NMR operating frequencies much greater than about 30 MHz, magnetic field amplitude and phase variations experienced by the nuclei may cause serious distortions in an image of a human torso. The maximum power deposition envisaged during an NMR imaging experiment on a human torso is likely to be comparable to existing long-term safe exposure levels, and will depend ultimately on the imaging technique and NMR frequency employed.

Animals↗
PubMed2026

TPMM: three-component posterior mixture model enables robust inverton detection in low-depth metagenomes and suggests potential viral invertons.

SUMMARY: Bacterial phase variation enables reversible, locus-specific phenotypic switching, often driven by DNA inversion (invertons). To identify these events, researchers commonly rely on sequencing reads that provide orientation-specific support. Metagenomic sequencing, which captures total genetic material independent of cultivation, offers a powerful platform for the comprehensive study of invertons. However, computational inverton calling from metagenomic data is difficult at low sequencing depth: hard read-support cutoffs can miss true events, while sequence-only predictors lack read-backed interpretability and uncertainty quantification. To address this, we present TPMM, a three-component posterior mixture model for inverton calling in metagenomic data. TPMM explicitly incorporates sequencing depth to formulate inverton detection as a probabilistic mixture problem. Starting from candidates flanked by inverted repeats, the model classifies the candidates into noise, low-probability, or high-probability inversion signals using read evidence. Finally, TPMM assigns posterior probabilities as soft labels and applies cumulative Bayesian False Discovery Rate control to robustly identify true invertons. On two real gut metagenomic datasets, TPMM agrees well with PhaseFinder at high depth but recovers substantially more invertons under systematic downsampling, demonstrating superior performance in sparse-data regimes. We further examine potential reversible inversion elements in viral genomes and provide supporting analyses, suggesting a broader scope for inversion-mediated regulation. AVAILABILITY: The source code of TPMM is available via: https://github.com/KennyxxD/TPMM.

Metagenomics↗
PubMed1975

Cell-envelope proteins of Bordetella pertussis.

Cell-envelope polypeptides of eight phase-I and five phase-IV strains of Bordetella pertussis were compared by SDS-polyacrylamide gel electrophoresis. All phase-I strains gave a strikingly similar but complex pattern of protein bands, which did not appear to vary with known differences in heat-labile agglutinogens. Phase-IV strains gave the same pattern as phase-I strains, except that one band was missing and another was either much reduced or absent. Envelopes from phase-I strains grown in Hornibrook medium rich in Mg-2+ ions to produce "antigenically-modulated" C-mode cells gave a pattern of bands indistinguishable from phase-IV strains. A phase-IV strain grown in the high-Mg-2+ medium gave the same pattern of bands as when grown in unmodified Hornibrook medium. We suggest that the two polypeptide bands that show changes may be responsible for one or more of the immunological or physiopathological activities that are lost during phase variation and antigenic modulation in B. pertussis.

Allergens↗
PubMed1977

Isolation and characterization of Escherichia coli phase variants and mutants deficient in type 1 pilus production.

Type 1 pili of Escherichia coli are the prototype of the somatic class of pili found on many strains of bacteria. As a first step in the genetic analysis of type 1 piliation, an extensive series of nonpiliated derivatives of E. coli K-12 strain AW405, was characterized to produce attached or free pili when examined in the antiserum or appeared to produce attached or free pili when examined in the electron microscope. The derivatives fell into two classes; phase variants and mutants. Phase variants that formed colonies of two distinctive types, one associated with a predominantly piliated (P+), and the other associated with a nonpiliated (P-) phase, were obtained. Each phase could give rise to the other at a relatively high rate, which was greater in the P- to P+ direction during culture in unshaken liquid medium. In addition, 77 Pil- mutants were selected on the basis of a subtle difference in colonial morphology. The mutants reverted, if at all, at a much lower rate than that of the P- to P+ change. The stability of Pil- derivatives grown in unshaken liquid medium was used as a criterion for distinguishing between phase variants and mutants, Phase variation also effected colonial morphology and chemotactic swarming. These properties did not directly depend upon piliation since Pil- mutants were only slightly altered in colonial form and unaltered in chemotactic swarming. Piliation of Pil+ bacteria was quantitatively affected by growth conditions.

Chemotaxis↗
PubMed1979

Serotyping of Serratia marcescens: current status of seven recently described flagellar (H) antigens.

The slightly revised, current scheme of 20 flagellar (H) antigens of Serratia marcesens was examined. The seven new H antigens were demonstrated to be antigenically distinct as determined with Le Minor's H-immobilization test. The H-immobilization antibodies of rabbit anti-H immune sera proved resistant to treatment with 2-mercaptoethanol and dithiothreitol, respectively. On the other hand, dual absorptions of rabbit anti-H immune sera with killed cells of Staphylococcus aureus strain Cowan I, i.e., protein A, failed to reduce significantly H-immobilization titers of rabbit sera, although human immunoglobulins G and M were bound by protein A. It was tentatively concluded that the 2-mercaptoethanol- and dithiothreitol-refractory H-immobilizing rabbit antibodies belonged to the immunoglublin M class. H-antigen (phase) variation was not demonstrable in several extramural, clinical isolates of S. marcescens for which this phenomenon had been claimed. Rather, four of these six isolates were found to consist of cell populations of two distinct serotypes, as also borne out by bacteriocin typing; the flagellar H-antigens of the remaining two isolates were stable, with minor, hterologous H-antigen cross-reactivity.

Antigens, Bacterial↗
PubMed1977

Spatial frequency and light-spread descriptions of visual acuity and hyperacuity.

Resolution (visual acuity) and differential spatial localization (hyperacuity) targets were selected to allow rigorous psychophysical measurements as well as ready expression of both their spatial frequency spectrum and their retinal image light distribution. Thresholds were about 1 arc min for acuity and 4-6 arc sec for hyperacuity. As is consistent with the reciprocal relationship between the space and spatial frequency domains, the small locally restricted spatial differences between just distinguishable patterns are represented in the frequency domain by equally small differences, which are distributed over the entire spatial frequency spectrum. While they occur in many test situations, phase variations of spatial frequency components are not necessary for achieving optimum acuity and hyperacuity.

Female↗