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PubMed1998

Phosphorylcholine on the lipopolysaccharide of Haemophilus influenzae contributes to persistence in the respiratory tract and sensitivity to serum killing mediated by C-reactive protein.

Haemophilus influenzae undergoes phase variation in expression of the phosphorylcholine (ChoP) epitope, a structure present on several invasive pathogens residing in the human respiratory tract. In this study, structural analysis comparing organisms with and without this epitope confirmed that variants differ in the presence of ChoP on the cell surface-exposed outer core of the lipopolysaccharide. During nasopharyngeal carriage in infant rats, there was a gradual selection for H. influenzae variants that express ChoP. In addition, genotypic analysis of the molecular switch that controls phase variation predicted that the ChoP+ phenotype was predominant in H. influenzae in human respiratory tract secretions. However, ChoP+ variants of nontypable H. influenzae were more sensitive to the bactericidal activity of human serum unrelated to the presence of naturally acquired antibody to ChoP. Serum bactericidal activity required the binding of C-reactive protein (CRP) with subsequent activation of complement through the classical pathway. Results of this study suggested that the ability of H. influenzae to vary expression of this unusual bacterial structure may correlate with its ability both to persist on the mucosal surface (ChoP+ phenotype) and to cause invasive infection by evading innate immunity mediated by CRP (ChoP- phenotype).

Amino Acid Sequence↗
PubMed1992

Fimbria-mediated adherence and hemagglutination of Haemophilus influenzae.

The gram-negative bacterium Haemophilus influenzae expresses morphologically and functionally distinct types of fimbriae, of which the LKP fimbriae mediate hemagglutination and adherence to human epithelial cells but hamper mucosal invasion. Therefore, the both in vivo and in vitro observed fimbrial phase variation may contribute to the pathogenesis of the infection. The existence of greater than 14 LKP serotypes hampers vaccine development based on fimbriae, since a monovalent fimbria vaccine confers protection against only the homologous strain. Cloning of the fimbrial genes in Escherichia coli results in the expression of morphologically intact fimbriae. Analysis of the cloned DNA indicates that a fimbrial gene cluster is necessary for formation of complete fimbriae and for fimbria-mediated adherence. The gene encoding the subunit is highly conserved among H. influenzae and belongs to the family of E. coli fimbriae. The phase variation is transcriptionally regulated by variation of the length of the reiterated sequence that forms the promoter region of the subunit gene.

Animals↗
PubMed1990

Identification of an Escherichia coli genetic locus involved in thermoregulation of the pap operon.

We previously showed, using a single-copy papBAp-lac fusion (previously designated papBA-lac), that pyelonephritis-associated pili (pap) pilin gene transcription is subject to both phase variation and thermoregulatory control mechanisms (L. B. Blyn, B. A. Braaten, C. A. White-Ziegler, D. H. Rolfson, and D. A. Low, EMBO J. 8:613-620, 1989). At 37 degrees C, Escherichia coli strains carrying the papBAp-lac fusion displayed both Lac+ and Lac- colony phenotypes. In contrast, at 23 degrees C, colonies displayed a uniform Lac- phenotype, suggesting that pilin was not transcribed at this temperature. In this study, a strain carrying the papBAp-lac fusion was subjected to mini-Tn10 (mTn10) mutagenesis to isolate mutants that could initiate transcription of pilin at the nonpermissive temperature. Two classes of thermoregulatory mutants were identified in which the mTn10 mutation was linked to the mutant phenotype. Class I mutants displayed a phase variation phenotype at both 37 degrees C and 23 degrees C, whereas class II mutants displayed a uniform Lac+ colony phenotype at both temperatures. Preliminary analysis of these mutants showed that the mTn10 insertions in the class I mutants were chromosomally located, whereas the mTn10 insertions in the class II mutants were located within the papBAp-lac fusion phage. Southern blot analysis of the class I mutants demonstrated that mTn10 was present in the same 5.9-kilobase SalI DNA fragment in each mutant. Two of the class I mTn10 mutations were mapped to approximately 23.4 min on the E. coli K-12 chromosome. The locus defined by the class I mTn10 mutations was designated tcp, for thermoregulatory control of pap. Analysis of phase transition rates of the class I mutants showed that the phase-off (Lac-)----phase-on (Lac+) transition rates were higher than those observed with the nonmutant E. coli strain.

Blotting, Southern↗
PubMed2001

Two-step navigatorless correction algorithm for radial k-space MRI acquisitions.

A new way to correct magnetic resonance image artifacts resulting from view-dependent phase variations and view-dependent variations in rigid body object translation is presented by exploiting basic properties of the trajectory of radial k-space acquisitions. Simulations, phantom studies, and in vivo experiments are used to demonstrate the feasibility and the utility of this method. While somewhat analogous to navigator echo correction, in which special gradients are interleaved into the imaging sequence so echoes at the center of k-space can be acquired prior to or after collection of the image data, the current method does not require additional new gradient structures within the pulse sequence or increases in scan time. The new method uses the phase information from all collected radial k-space data points rather than only the navigator echo, which permits correction of multiple sources of view-dependent phase variation in the image data. The resultant effect is improved image quality in radial MRI acquisitions. Magn Reson Med 45:277-288, 2001.

Algorithms↗
PubMed2001

Coupled phase-variable expression and epitope masking of selective surface lipoproteins increase surface phenotypic diversity in Mycoplasma hominis.

A new mechanism expanding mycoplasmal surface diversity is described. Exposure of surface epitopes on a constitutively expressed membrane protein (P56) of Mycoplasma hominis was subject to high-frequency phase variation due to phase-variable expression of the P120 antigen and its selective masking of P56 epitopes. Phase-variable masking may confer previously unrealized adaptive capabilities on mycoplasmas.

Antigenic Variation↗
PubMed2006

Lung deformation estimation and four-dimensional CT lung reconstruction.

RATIONALE AND OBJECTIVES: Four-dimensional (4D) computed tomography (CT) can be used in radiation treatment planning to account for respiratory motion. Current 4D CT techniques have limitations in either spatial or temporal resolution. In addition, most of these techniques rely on auxiliary surrogates to relate the time of the CT scan to the patient's respiratory phase. We propose a 4D CT method for lung applications to overcome these problems. MATERIALS AND METHODS: A set of axial scans are taken at multiple table positions to obtain a series of two-dimensional images while the patient is breathing freely. Each two-dimensional image is registered to a reference CT volume. The deformation of the image with respect to the volume is used to synchronize the image with the respiratory cycle assuming that there is no phase variation along the craniocaudal direction. The reconstructed 4D dataset is a series of deformable transformations of the reference volume. RESULTS: A synthetic 4D dataset showed that the registration error is less than 5% of the image deformation. A swine study showed that the algorithm can generate better image quality than the image sorting method. A respiratory-gated 4D dataset showed that the algorithm's result is consistent with the ground truth. CONCLUSION: The algorithm can reconstruct good quality 4D images without external surrogates even if the CT scans are acquired under irregular respiratory motion. The algorithm may allow for reduced radiation dose to the patient with a limited loss of image quality. Although the phase variation exists along the craniocaudal direction, the 4D reconstruction is reasonably accurate.

Algorithms↗
PubMed1999

Growth phase-dependent variation in protein composition of the Escherichia coli nucleoid.

The genome DNA of Escherichia coli is associated with about 10 DNA-binding structural proteins, altogether forming the nucleoid. The nucleoid proteins play some functional roles, besides their structural roles, in the global regulation of such essential DNA functions as replication, recombination, and transcription. Using a quantitative Western blot method, we have performed for the first time a systematic determination of the intracellular concentrations of 12 species of the nucleoid protein in E. coli W3110, including CbpA (curved DNA-binding protein A), CbpB (curved DNA-binding protein B, also known as Rob [right origin binding protein]), DnaA (DNA-binding protein A), Dps (DNA-binding protein from starved cells), Fis (factor for inversion stimulation), Hfq (host factor for phage Q(beta)), H-NS (histone-like nucleoid structuring protein), HU (heat-unstable nucleoid protein), IciA (inhibitor of chromosome initiation A), IHF (integration host factor), Lrp (leucine-responsive regulatory protein), and StpA (suppressor of td mutant phenotype A). Intracellular protein levels reach a maximum at the growing phase for nine proteins, CbpB (Rob), DnaA, Fis, Hfq, H-NS, HU, IciA, Lrp, and StpA, which may play regulatory roles in DNA replication and/or transcription of the growth-related genes. In descending order, the level of accumulation, calculated in monomers, in growing E. coli cells is Fis, Hfq, HU, StpA, H-NS, IHF*, CbpB (Rob), Dps*, Lrp, DnaA, IciA, and CbpA* (stars represent the stationary-phase proteins). The order of abundance, in descending order, in the early stationary phase is Dps*, IHF*, HU, Hfq, H-NS, StpA, CbpB (Rob), DnaA, Lrp, IciA, CbpA, and Fis, while that in the late stationary phase is Dps*, IHF*, Hfq, HU, CbpA*, StpA, H-NS, CbpB (Rob), DnaA, Lrp, IciA, and Fis. Thus, the major protein components of the nucleoid change from Fis and HU in the growing phase to Dps in the stationary phase. The curved DNA-binding protein, CbpA, appears only in the late stationary phase. These changes in the composition of nucleoid-associated proteins in the stationary phase are accompanied by compaction of the genome DNA and silencing of the genome functions.

Bacterial Proteins↗
PubMed1985

Population shift in mannose-specific fimbriated phase of Klebsiella pneumoniae during experimental urinary tract infection in mice.

The infection rate (percentage of mice shedding 10(5) organisms per ml of urine) in 27 mice infected intravesicularly with a mannose-specific (MS+) phenotype of Klebsiella pneumoniae was 85% at day 7, and all the bacteria shed during the 7 days exhibited strong MS activity as estimated by a yeast aggregation assay. In contrast, the outcome of infection with an MS- phenotype of the same strain in 47 mice was heterogeneous: one group of 25 mice continued to shed the originally injected phenotype (MS-) throughout the investigation period, whereas the second group (22 mice) shed bacteria with various degrees of phenotypic conversion to MS+. In the first group, the rate of infection at day 7 was significantly reduced (28%) compared with that of the second group (68%). Mice infected with a mixture of 5% MS+ bacteria and 95% of an MS- variant which lost its ability to undergo phase variation had an infection rate of 89%, but at day 7 95% of the excreted bacteria were MS+. The infection rate of mice injected with the MS- variant was 14%, and none of the mice shed MS+ bacteria. The incidence of kidney pathology was higher in mice inoculated with the MS+ phenotype (3 of 10) or in the group in which the MS+ overgrew the MS- phenotype (4 of 10) as compared with the group of mice in which no such shift occurred (1 of 11). The kidneys of four mice which excreted mostly MS+ organisms harbored a population predominantly of the MS- phenotype. These results suggest that the MS adhesin confers an advantage in the initial steps of the infectious process in the bladder but not in later stages of infection in the kidney, emphasizing the importance of phase variation in the survival of bacteria at the various stages of the infectious process.

Adhesiveness↗
PubMed1990

The osmZ (bglY) gene encodes the DNA-binding protein H-NS (H1a), a component of the Escherichia coli K12 nucleoid.

A class of trans-acting mutations, which alter the osmoregulated expression of the Escherichia coli proU operon, maps at 27 min on the chromosome in a locus we have called osmZ. Mutations in osmZ are allelic to bglY, pilG and virR, affect gene expression, increase the frequency of the site-specific DNA inversion mediating fimbrial phase variation, stimulate the formation of deletions, and influence in vivo supercoiling of reporter plasmids. We have cloned the osmZ+ gene, mapped it at 1307 kb of the E. coli restriction map, identified its gene product as a 16 kDa protein, and determined the nucleotide sequence of the osmZ+ gene. The deduced amino acid sequence for OsmZ predicts a protein of 137 amino acid residues with a calculated molecular weight of 15,530. The primary sequence of OsmZ is identical to that of H-NS (H1a), a DNA-binding protein that affects DNA topology and is known to be associated with the bacterial nucleoid. Thus, osmZ is the structural gene for the H-NS (H1a) protein. The nucleotide sequence of osmZ is almost identical to that of hns; however, hns was incorrectly located at 6.1 min on the E. coli linkage map. Increased osmZ gene dosage leads to cell filament formation, altered gene expression, and reduced frequency of fimbrial phase variation. Our results suggest that the nucleoid-associated DNA-binding protein H-NS (H1a) plays a critical role in gene expression and in determining the structure of the genetic material.

Alleles↗
PubMed2000

Concerted evolution of duplicate fla genes in Campylobacter.

Campylobacters have two similar copies (flaA and flaB) of their flagellin gene. It has been hypothesized that the two copies can serve for antigenic phase variation. Analysis of polymorphisms within aligned multiple DNA sequences of the Campylobacter flagellin genes revealed high pairwise homoplasy indexes between flaB/flaB pairs that were not observed between any flaA/flaA pairings or flaA/flaB pairings. Thus it seems there are constraints on the sequence of flaB that distinguish it from flaA. Nevertheless, segments of the two genes that are highly variable between strains are conserved between the flaA and flaB copies of the genes within a strain. The patterns of synonymous and non-synonymous differences suggest that one segment of the flagellin sequence is under selective pressure at the amino acid sequence level. Another segment of the protein is maintained within a strain by conversion or recombination. Comparisons of strict consensus amino acid sequences did not reveal any motifs that are uniquely FlaA or FlaB, but there are differences between FlaA and FlaB in those amino acids available for post-translational modification. The observed pattern of concerted evolution of portions of a structural gene is an unusual finding in bacteria and should be searched for with other duplicated genes. Concerted evolution was unexpected for genes involved in phase variation since it minimizes the antigenic repertoire that can be expressed by a single clone in the face of the host immune response.

Amino Acid Sequence↗
PubMed2004

Differences in membrane fluidity and fatty acid composition between phenotypic variants of Streptococcus pneumoniae.

Phase variation in the colonial opacity of Streptococcus pneumoniae has been implicated as a factor in the pathogenesis of pneumococcal disease. This study examined the relationship between membrane characteristics and colony morphology in a few selected opaque-transparent couples of S. pneumoniae strains carrying different capsular types. Membrane fluidity was determined on the basis of intermolecular excimerization of pyrene and fluorescence polarization of 1,6-diphenyl 1,3,5-hexatriene (DPH). A significant decrease, 16 to 26% (P < or = 0.05), in the excimerization rate constant of the opaque variants compared with that of the transparent variants was observed, indicating higher microviscosity of the membrane of bacterial cells in the opaque variants. Liposomes prepared from phospholipids of the opaque phenotype showed an even greater decrease, 27 to 38% (P < or = 0.05), in the pyrene excimerization rate constant compared with that of liposomes prepared from phospholipids of bacteria with the transparent phenotype. These findings agree with the results obtained with DPH fluorescence anisotropy, which showed a 9 to 21% increase (P < or = 0.001) in the opaque variants compared with the transparent variants. Membrane fatty acid composition, determined by gas chromatography, revealed that the two variants carry the same types of fatty acids but in different proportions. The trend of modification points to the presence of a lower degree of unsaturated fatty acids in the opaque variants compared with their transparent counterparts. The data presented here show a distinct correlation between phase variation and membrane fluidity in S. pneumoniae. The changes in membrane fluidity most probably stem from the observed differences in fatty acid composition.

Cell Membrane↗
PubMed2005

Survival strategies of infectious biofilms.

Modern medicine is facing the spread of biofilm-related infections. Bacterial biofilms are difficult to detect in routine diagnostics and are inherently tolerant to host defenses and antibiotic therapies. In addition, biofilms facilitate the spread of antibiotic resistance by promoting horizontal gene transfer. We review current concepts of biofilm tolerance with special emphasis on the role of the biofilm matrix and the physiology of biofilm-embedded cells. The heterogeneity in metabolic and reproductive activity within a biofilm correlates with a non-uniform susceptibility of enclosed bacteria. Recent studies have documented similar heterogeneity in planktonic cultures. Nutritional starvation and high cell density, two key characteristics of biofilm physiology, also mediate antimicrobial tolerance in stationary-phase planktonic cultures. Advances in characterizing the role of stress response genes, quorum sensing and phase variation in stationary-phase planktonic cultures have shed new light on tolerance mechanisms within biofilm communities.

Adaptation, Physiological↗
PubMed1997

Virulence mechanisms of avian fimbriated Escherichia coli in experimentally inoculated chickens.

Virulence mechanisms of avian pathogenic Escherichia coli were investigated by inoculating commercial broiler chickens via the left caudal thoracic air sac with three highly pathogenic and three less pathogenic E. coli isolates. At 6 h postinoculation, all isolates had colonized the respiratory tract (trachea, lungs, and air sacs) and internal organs (liver, spleen, and kidney) of inoculated birds, but bacteria were recovered from pericardial fluid and blood only of birds inoculated with the more pathogenic isolates. F1 fimbriae were expressed on a high proportion of bacteria colonizing the trachea and to a lesser extent on bacteria in the lungs of birds inoculated with each of the isolates. F1 fimbriae were also expressed on bacteria in air sacs only for the less pathogenic isolates. P(F11) fimbriae were expressed on bacteria present in air sacs, lungs, kidney, blood, and pericardial fluid of birds inoculated with one of the more virulent isolates. On electron microscopy, bacteria of the more pathogenic isolates but not of the less pathogenic isolates were observed often associated with or within macrophages, which appeared to be viable, in the air sacs and lungs. In in vitro assays, the more pathogenic but not the less pathogenic isolates, were resistant to opsonization and phagocytosis in the absence of F1 fimbriae, whereas bacteria of all isolates were rapidly killed by avian macrophages when they expressed F1 fimbriae. These results suggest that resistance to phagocytosis may be an important mechanism in avian colisepticemia. They also suggest that F1 fimbrial phase variation to the nonfimbriated phase is favored in the avian lower respiratory tract, is more marked for the more pathogenic-isolates, and may be a virulence mechanism.

Air Sacs↗