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Biomedical subjects

Andrew Preston

Publications and source records attributed to Andrew Preston.

9 recordsLinked to original sources
PubMed2003

Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica.

Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica are closely related Gram-negative beta-proteobacteria that colonize the respiratory tracts of mammals. B. pertussis is a strict human pathogen of recent evolutionary origin and is the primary etiologic agent of whooping cough. B. parapertussis can also cause whooping cough, and B. bronchiseptica causes chronic respiratory infections in a wide range of animals. We sequenced the genomes of B. bronchiseptica RB50 (5,338,400 bp; 5,007 predicted genes), B. parapertussis 12822 (4,773,551 bp; 4,404 genes) and B. pertussis Tohama I (4,086,186 bp; 3,816 genes). Our analysis indicates that B. parapertussis and B. pertussis are independent derivatives of B. bronchiseptica-like ancestors. During the evolution of these two host-restricted species there was large-scale gene loss and inactivation; host adaptation seems to be a consequence of loss, not gain, of function, and differences in virulence may be related to loss of regulatory or control functions.

Base Sequence↗
PubMed2003

Bordetella bronchiseptica PagP is a Bvg-regulated lipid A palmitoyl transferase that is required for persistent colonization of the mouse respiratory tract.

Bordetella bronchiseptica lipopolysaccharide (LPS) expression varies depending on growth conditions, regulated by the Bvg system. A B. bronchiseptica pagP homologue was identified that is required for Bvg-mediated modification of the lipid A core region of LPS that occurs on switching from the Bvg- to the Bvg+ phase. Structural analysis demonstrated that the lipid A of a B. bronchiseptica pagP mutant differed from wild-type lipid A by the absence of a palmitate group in secondary acylation at the C3' position. The putative pagP promoter drove the expression of a green fluorescent protein (GFP) reporter gene in a Bvg-regulated fashion. These data suggest that B. bronchiseptica pagP encodes a Bvg-regulated lipid A palmitoyl transferase that mediates modification of the lipid A as part of the overall Bvg-mediated adaptation of this organism to changing environmental conditions. We also show that pagP is not required for the initial colonization of the mouse respiratory tract by B. bronchiseptica, but is required for persistence of the organism within this organ.

Acyltransferases↗
PubMed2003

Role of Bordetella O antigen in respiratory tract infection.

Lipopolysaccharide (LPS), as the major surface molecule of gram-negative bacteria, interacts with the host in complex ways, both inducing and protecting against aspects of inflammatory and adaptive immunity. The membrane-distal repeated carbohydrate structure of LPS, the O antigen, can prevent antibody functions and may vary as a mechanism of immune evasion. Genes of the wbm locus are required for the assembly of O antigen on the animal pathogen Bordetella bronchiseptica and the human pathogen B. parapertussis. However, the important human pathogen B. pertussis lacks these genes and a number of in vitro and in vivo characteristics associated with O antigen in other organisms. To determine the specific functions of O antigen in these closely related Bordetella subspecies, we compared wbm deletion (Deltawbm) mutants of B. bronchiseptica and B. parapertussis in a variety of assays relevant to natural respiratory tract infection. Complement was not activated or depleted by wild-type bordetellae expressing O antigen, but both Deltawbm mutants activated complement and were highly sensitive to complement-mediated killing in vitro. Although the O-antigen structures appear to be substantially similar, the two mutants differed strikingly in their defects within the respiratory tract. The B. parapertussis Deltawbm mutant was severely defective in colonization of the tracheas and lungs of mice, while the B. bronchiseptica Deltawbm mutant showed almost no defect. While in vitro characteristics such as serum resistance may be attributable to O antigen directly, the role of O antigen during infection appears to be more complex, possibly involving factors differing among the closely related bordetellae or different interactions between each one and its host.

Animals↗
PubMed2002

Reverse transcriptase-mediated tropism switching in Bordetella bacteriophage.

Host-pathogen interactions are often driven by mechanisms that promote genetic variability. We have identified a group of temperate bacteriophages that generate diversity in a gene, designated mtd (major tropism determinant), which specifies tropism for receptor molecules on host Bordetella species. Tropism switching is the result of a template-dependent, reverse transcriptase-mediated process that introduces nucleotide substitutions at defined locations within mtd. This cassette-based mechanism is capable of providing a vast repertoire of potential ligand-receptor interactions.

Bacteriophages↗
PubMed2002

Relaxed acyl chain specificity of Bordetella UDP-N-acetylglucosamine acyltransferases.

Lipid A (endotoxin) is a major structural component of Gram-negative outer membranes. It also serves as the hydrophobic anchor of lipopolysaccharide and is a potent activator of the innate immune response. Lipid A molecules from the genus Bordetella are reported to exhibit unusual structural asymmetry with respect to the acyl chains at the 3- and 3'-positions. These acyl chains are attached by UDP-N-acetylglucosamine acyltransferase (LpxA). To determine the origin of the acyl variability, the single lpxA ortholog present in each of the genomes of Bordetella bronchiseptica (lpxA(Br)), Bordetella parapertussis (lpxA(Pa)), and Bordetella pertussis (lpxA(Pe)) was cloned and expressed in Escherichia coli. In contrast to all LpxA proteins studied to date, LpxA(Br) and LpxA(Pe) display relaxed acyl chain length specificity in vitro, utilizing C(10)OH-ACP, C(12)OH-ACP, and C(14)OH-ACP at similar rates. Furthermore, hybrid lipid A molecules synthesized at 42 degrees C by an E. coli lpxA mutant complemented with lpxA(Pe) contain C(10)OH, C(12)OH, and C(14)OH at both the 3- and 3'-positions, as determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In contrast, LpxA from B. parapertussis did not display relaxed specificity but was selective for C(10)OH-ACP. This study provides an enzymatic explanation for some of the unusual acyl chain variations found in Bordetella lipid A.

Acyltransferases↗
PubMed2002

Effect of a GP desktop resource on smoking cessation activities of general practitioners.

OBJECTIVES: To evaluate an intervention aimed at increasing the quantity and quality of brief opportunistic general practitioner (GP) advice to smokers encouraging and supporting quit attempts. DESIGN: Randomized controlled trial with two groups: (1) control and (2) GP desktop resource (GDR). Smoking cessation activities of GPs were assessed by an independent postal survey 1 month after distribution of resource. SUBJECTS AND SETTING: One hundred and seven GPs in West Dorset. MAIN OUTCOME MEASURES: GPs' self-reported rates of advising and counselling smokers on cessation over the previous week. RESULTS: The rate of opportunistic advice per week in the GDR group was 4.9 (SD = 4.1), compared with 2.8 (SD = 1.8) in the control group, F = 8.2, p = 0.0025, one-tailed. The rate of giving counselling was also higher 2.2 (SD = 3.2) in the intervention group versus 1.0 (SD = 1.4) in the control group, F = 4.0), p = 0.025, one-tailed. The proportion who had recommended or prescribed NRT was greater, although not significantly (54%, versus 46%, Fisher's exact p = 0.1, one-tailed). CONCLUSIONS: The findings indicate that the GDR can increase the rate of delivery of opportunistic advice and provision of counselling. Given the importance of this activity, a larger trial appears to be warranted to examine the long-term effect and the effect on cessation rates in patients.

Counseling↗
PubMed2002

Molecular genetics and role in infection of environmentally regulated lipopolysaccharide expression.

Lipopolysaccharides (LPSs) from different Gram-negative bacteria are structurally distinct. Even closely related serovars of single bacterial species may possess different LPS molecules. Further variability may then be superimposed on this ground-state structural diversity as a result of variable expression of other LPS structures. This variable expression is due in some cases to high-frequency, reversible, random "on-off" switching of genes required for biosynthesis of particular LPS structures. In other cases differential expression of LPS biosynthesis genes may be part of a programmed response to environmental stimuli, which may occur as adaptations by pathogenic bacteria to changing environments within the host during the course of infection.

Antigenic Variation↗