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B F Cheetham

Publications and source records attributed to B F Cheetham.

At least 19 recordsLinked to original sources

Improved diagnosis of virulent ovine footrot using the intA gene.

Footrot is a mixed bacterial infection of the hooves of sheep. The gram-negative anaerobic bacterium Dichelobacter nodosus is the principal causative agent, with different strains causing diseases of different severity, ranging from benign to virulent. In Australia, in the state of New South Wales (NSW), only virulent footrot is subject to regulatory action, including quarantine. However, it is often difficult to distinguish benign footrot from virulent footrot in the initial stages of infection, or under adverse climatic conditions. The gelatin gel test, which measures the thermostability of secreted bacterial proteases, is the laboratory test most widely used in Australia to aid in the differential diagnosis of footrot. The proteases of virulent strains are, in general, more thermostable than the proteases of benign strains. However, there are some false positives in the gelatin gel test, which may lead to unnecessary quarantine procedures. We used Southern blot analysis on 595 isolates of D. nodosus from 124 farms on which sheep had benign or virulent footrot to test for the presence of the intA gene. We found that for D. nodosus strains which are stable in the gelatin gel test, there is a high correlation between the presence of the intA gene and the ability of the strain to cause virulent footrot. We also developed a PCR-based assay for the rapid detection of intA, which can be used to test DNA extracted from colonies grown on plates, or DNA extracted from cotton swabs of culture plates.

Animals↗

Analysis of two Aspergillus nidulans genes encoding extracellular proteases.

Characterization of prtADelta mutants, generated by gene disruption, showed that the prtA gene is responsible for the majority of extracellular protease activity secreted by Aspergillus nidulans at both neutral and acid pH. The prtA delta mutation was used to map the prtA gene to chromosome V. Though aspartic protease activity has never been reported in A. nidulans and the prtADelta mutants appear to lack detectable acid protease activity, a gene (prtB) encoding a putative aspartic protease was isolated from this species. Comparison of the deduced amino acid sequence of PrtB to the sequence of other aspergillopepsins suggests that the putative prtB gene product contains an eight-amino-acid deletion prior to the second active site Asp residue of the protease. RT-PCR experiments showed that the prtB gene is expressed, albeit at a low level.

Amino Acid Sequence↗

Identification and characterization of a native Dichelobacter nodosus plasmid, pDN1.

The gram-negative anaerobe Dichelobacter nodosus is the primary causative agent of ovine footrot, a mixed bacterial infection of the hoof. We report here the characterization of a novel native plasmid, pDN1, from D. nodosus. Sequence analysis has revealed that pDN1 has a high degree of similarity to broad-host-range plasmids belonging, or related, to Escherichia coli incompatibility group Q. However, in contrast to these plasmids, pDN1 encodes no antibiotic resistance determinants, lacks genes E and F, and hence is smaller than all previously reported IncQ plasmids. In addition, pDN1 belongs to a different incompatibility group than the IncQ plasmids to which it is related. However, pDN1 does contain the replication and mobilization genes that are responsible for the extremely broad host range characteristic of IncQ plasmids, and derivatives of pDN1 replicate in E. coli. In addition, the mobilization determinants of pDN1 are functional, since derivatives of pDN1 are mobilized by the IncPalpha plasmid RP4 in E. coli.

Bacterial Proteins↗

The Aspergillus nidulans xprF gene encodes a hexokinase-like protein involved in the regulation of extracellular proteases.

The extracellular proteases of Aspergillus nidulans are produced in response to limitation of carbon, nitrogen, or sulfur, even in the absence of exogenous protein. Mutations in the A. nidulans xprF and xprG genes have been shown to result in elevated levels of extracellular protease in response to carbon limitation. The xprF gene was isolated and sequence analysis indicates that it encodes a 615-amino-acid protein, which represents a new type of fungal hexokinase or hexokinase-like protein. In addition to their catalytic role, hexokinases are thought to be involved in triggering carbon catabolite repression. Sequence analysis of the xprF1 and xprF2 alleles showed that both alleles contain nonsense mutations. No loss of glucose or fructose phosphorylating activity was detected in xprF1 or xprF2 mutants. There are two possible explanations for this observation: (1) the xprF gene may encode a minor hexokinase or (2) the xprF gene may encode a protein with no hexose phosphorylating activity. Genetic evidence suggests that the xprF and xprG genes are involved in the same regulatory pathway. Support for this hypothesis was provided by the identification of a new class of xprG(-) mutation that suppresses the xprF1 mutation and results in a protease-deficient phenotype.

Alleles↗

The site-specific integration of genetic elements may modulate thermostable protease production, a virulence factor in Dichelobacter nodosus, the causative agent of ovine footrot.

The gram-negative anaerobe Dichelobacter nodosus is the causative agent of footrot in sheep. The authors have previously characterized two genetic elements, the intA (vap) and intB elements, which integrate into the genome of D. nodosus. In the virulent strain A198 there are two copies of the intA element. One copy is integrated into the 3' end of the tRNA-serGCU gene, close to the aspartokinase (askA) gene, and the second copy is integrated into the 3' end of the tRNA-serGGA gene, next to the polynucleotide phosphorylase (pnpA) gene. In this study, a new genetic element was identified in the benign strain C305, the intC element, integrated into the 3' end of the tRNA-serGCU gene, next to askA. The intC element was found in most D. nodosus strains, both benign and virulent, which were examined, and was integrated into tRNA-serGCU in most strains. Between the askA and tRNA-serGCU genes, a gene (designated glpA), was identified whose predicted protein product has very high amino acid identity with RsmA from the plant pathogen Erwinia carotovora. RsmA acts as a global repressor of pathogenicity in E. carotovora, by repressing the production of extracellular enzymes. In virulent strains of D. nodosus the intA element was found to be integrated next to pnpA, and either the intA or intC element was integrated next to glpA. By contrast, all but one of the benign strains had intB at one or both of these two positions, and the one exception had neither intA, intB nor intC at one position. The loss of the intC element from the virulent strain 1311 resulted in loss of thermostable protease activity, a virulence factor in D. nodosus. A model for virulence is proposed whereby integration of the intA and intC genetic elements modulates virulence by altering the expression of glpA, pnpA, tRNA-serGCU and tRNA-serGGA.

3' Untranslated Regions↗

Extreme DNA sequence variation in isolates of Aspergillus fumigatus.

DNA sequence analysis of the alkaline protease gene was used to investigate two Aspergillus fumigatus strains isolated from ostriches (QLD1 and NSW3) and one environmental isolate (FRR 1266) that have shown genetic variation in previous analyses. The results showed that the QLD1 sequence was virtually identical to the published sequences for three human isolates but NSW3 differed in > 6% and FRR 1266 in > 10% of the nucleotides that were analysed. An RFLP assay was designed to determine the distribution of these (and other) genetic variants among environmental and clinical isolates of A. fumigatus.

Amino Acid Sequence↗

Identification of a native Dichelobacter nodosus plasmid and implications for the evolution of the vap regions.

Studies on the role of various virulence factors of the ovine pathogen, Dichelobacter nodosus, have suffered from the absence of a mechanism for the introduction of DNA into this organism. As an initial step in the development of genetic methods, we have identified and cloned a native 10-kb plasmid, pJIR896, from a clinical isolate. This plasmid was found to be a circular form of vap region 1/3 that is found in the reference strain, A198. However, pJIR896 lacked the duplicated region present in the A198 sequence and instead contained a 1.7-kb putative insertion sequence, IS1253, which shared similarity to a number of unusual IS elements. A model is proposed for the evolution of vap region 1/3 which involves the integration of a plasmid, such as pJIR896, and subsequent rearrangements resulting from the deletion or transposition of IS1253.

Base Sequence↗

Mutations affecting extracellular protease production in the filamentous fungus Aspergillus nidulans.

The extracellular proteases of Aspergillus nidulans are known to be regulated by carbon, nitrogen and sulphur metabolite repression. In this study, a mutant with reduced levels of extracellular protease was isolated by screening for loss of halo production on milk plates. Genetic analysis of the mutant showed that it contains a single, recessive mutation, in a gene which we have designated xprE, located on chromosome VI. The xprE1 mutation affected the production of extracellular proteases in response to carbon, nitrogen and, to a lesser extent, sulphur limitation. Three reversion mutations, xprF1, xprF2 and xprG1, which suppress xprE1, were characterised. Both xprF and xprG map to chromosome VII but the two genes are unlinked. The xprF1, xprF2 and xprG1 mutants showed high levels of milk-clearing activity on medium containing milk as a carbon source but reduced growth on a number of nitrogen sources. Evidence is presented that the xprE1 and xprG1 mutations alter expression of more than one protease and affect levels of alkaline protease gene mRNA.

Aspergillus nidulans↗

Development of a method for the identification, using the polymerase chain reaction, of Aspergillus fumigatus isolated from ostriches.

OBJECTIVE: To develop a method for identifying DNA of Aspergillus fumigatus from ostriches, using the polymerase chain reaction (PCR). A fumigatus is the principal causative agent of avian aspergillosis. DESIGN: A biochemical trial. SAMPLE POPULATION: Twelve Aspergillus fumigatus isolates and three other Aspergillus species. PROCEDURE: PCR primers that were based on the sequence of the alkaline protease gene from human isolates of A fumigatus were used. RESULTS: We successfully tested the method on ostrich isolates from five states and showed that the test is specific for A fumigatus. CONCLUSIONS: In most cases the DNA sequence of A fumigatus isolates from ostriches is similar to that of human isolates. DNA sequences vary significantly among A fumigatus isolates, including those from affected ostriches in the same flock. The genetic variation may be used to trace aspergillus infections in ostrich flocks and determine if the disease is transmitted by contact with infected birds.

Animals↗

Identification of a gene encoding a bacteriophage-related integrase in a vap region of the Dichelobacter nodosus genome.

Dichelobacter nodosus is the principal causative agent of ovine footrot. Nucleotide (nt) sequences from the D. nodosus genome have been isolated and a series of overlapping lambda clones defining vap (virulence-associated protein) regions 1, 2 and 3 have been reported [Katz et al., J. Bacteriol. 176 (1994) 2663-2669]. In the present study, the limits of the virulence-associated (va) DNA around vap regions 1 and 3 were determined by dot-blot hybridization experiments using plasmid subclones to probe genomic DNA from the D. nodosus virulent strain A198 and the benign strain C305. This va region was found to be approx. 11.9 kb in length, and to be interrupted by a short DNA segment which is also found in the benign D. nodosus strain. Sequence analysis of the entire region revealed an ORF, intA, which is very similar to the integrases of bacteriophages phi R73, P4 and Sf6. Bacteriophages phi R73 and P4 integrate into the 3' ends of tRNA genes, with the integrase genes adjacent to the tRNA genes. A similar arrangement was found in the D. nodosus va region. A 19-bp nt sequence was found to be repeated at the ends of the va region, and may represent the bacteriphage attachment site. These findings suggest that D. nodosus may have acquired these DNA sequences by the integration of a bacteriophage, or an integrative plasmid that contains a bacteriophage-related integrase gene. The high similarity of the D. nodosus integrase to integrases from coliphages suggests that these va sequences may be transferred between distantly related bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

A role for bacteriophages in the evolution and transfer of bacterial virulence determinants.

A virulence-associated region in the genome of Dichelobacter nodosus has been shown to contain an integrase gene which is highly related to the integrases of Shigella flexneri phage Sf6 and coliphages P4 and phi R73, together with open reading frames (vapB, C and D) related to genes borne on plasmids in Neisseria gonorrhoeae, Escherichia coli, Actinobacillus actinomycetemcomitans and Treponema denticola. Similar to P4 and phi R73, the vap region is bracketed by putative bacteriophage att sites and is adjacent to a tRNA gene, which suggests that the vap region has been derived by the integration of a bacteriophage, or a plasmid carrying a bacteriophage-related integrase gene. Many similarities in genes and genes clusters encoding virulence determinants have been found in distantly related bacteria. These genes are often located on plasmids in one organism but on the chromosome in others, implying that transmission of the genes has been followed by integration. Thus, the events which have generated the vap regions of D. nodosus may represent a common mechanism for transfer of virulence determinants. A number of genes involved in the virulence of bacterial pathogens are found on integrated bacteriophages, and we suggest that others will prove to be associated with tRNA genes and/or integrase genes derived from bacteriophages. The use of tRNA genes as integration sites for many bacteriophages and plasmids may favour intergeneric transmission, as tRNA genes are highly conserved.

Attachment Sites, Microbiological↗

Isolation and characterization of an Aspergillus nidulans gene encoding an alkaline protease.

We have cloned an Aspergillus nidulans gene (prtA) encoding an alkaline protease (Alp) by probing an A. nidulans library with a fragment amplified from an Aspergillus oryzae Alp-encoding gene. The nucleotide (nt) sequence of prtA was determined. The structure of prtA is similar to that of the A. oryzae Alp-encoding gene. The prtA gene is composed of four exons which are separated by three introns of 59, 57 and 54 nt. The deduced amino acid sequence of the prtA product shows a high degree of similarity to proteases from A. oryzae, A. fumigatus and A. flavus. Southern blot analysis suggests that only one copy of this gene is found in the genome of A. nidulans. The extracellular proteases of A. nidulans are regulated by nitrogen, carbon and sulfur metabolite repression. The prtA RNA levels were analysed under different nutrient conditions. No prtA transcript was detected in mycelium grown in medium containing glucose, NH4+ and sulfate. However, prtA transcript levels were high in mycelia transferred to medium lacking a nitrogen, carbon or sulfur source.

Amino Acid Sequence↗

Genetic organization of the duplicated vap region of the Dichelobacter nodosus genome.

The recombinant plasmid pJIR318 contains a fragment of the Dichelobacter nodosus genome which is associated with virulence. Sequence analysis of the pJIR318 insert has shown that it contains four vap (virulence-associated protein) genes which are homologous to open reading frames found on the Escherichia coli F plasmid and the Neisseria gonorrhoeae cryptic plasmid (M. E. Katz, R. A. Strugnell, and J. I. Rood, Infect. and Immun. 60:4586-4592, 1992). The plasmid pJIR318 hybridizes to three regions of the D. nodosus genome, each of which has now been isolated. Regions 1 and 3 were found to be adjacent in the genome of D. nodosus A198, and the order of the vap genes in vap regions 1 and 2 were shown to be identical. Partial sequence analysis and Southern blot analysis of the vap regions showed that the three regions probably arose by a duplication event(s) followed by insertions and/or deletions. A recombinant plasmid, pJIR749, was isolated from a library of a benign D. nodosus strain, 305. This plasmid contained sequences from both ends of vap region 2. Analysis of pJIR749 showed that the sequences on either side of vap region 2 were separated by 324 bp in the genome of benign strain 305 and that the orientations of the sequences were different. It is clear that a simple insertion or deletion event did not generate the benign and virulent strains studied. A model which describes the evolution of the duplicated vap regions in D. nodosus A198 is presented.

Bacteria, Anaerobic↗

Detection of human interferon-alpha-encoding gene expression.

We have devised a sensitive method based on the polymerase chain reaction (PCR) to detect expression of human interferon-alpha-encoding genes (IFN-A) in general, and specifically, expression of the IFN-A2 or IFN-A4 genes. The utility of the PCR approach was assessed by analysis of cloned IFN-A genes, as well as genomic DNA and mRNA isolated from peripheral blood mononuclear cells. We demonstrate the specific amplification of sequences encoding IFN subtypes IFN-alpha-2 and IFN-alpha-4 from as little as 0.1 pg of IFN-A mRNA. The PCR technique has potential clinical application for the detection of IFN-A expression and, thus, identification of the IFN-alpha subtypes produced, particularly in small biopsy samples or otherwise, where only low numbers of cells are available.

Base Sequence↗

Molecular detection of interferon-alpha expression in multiple sclerosis brain.

The demonstration of intermittent interferonaemia in patients with multiple sclerosis prompted a molecular analysis of brain tissue for expression of interferon-alpha genes. A sensitive method was developed based on the polymerase chain reaction. Primer sets were used that could amplify all interferons-alpha or two particular subtypes, interferon-alpha 2 and interferon-alpha 4. The procedure was successful in detecting expression of interferons-alpha in brain and non-brain tissues in most patients with multiple sclerosis. However, expression was demonstrable also in a similar proportion of patients with other neural diseases, and patients with other illnesses. The data indicate that there can be constitutive expression of interferons-alpha in brain tissue, but the possibility that this becomes amplified in multiple sclerosis was not revealed by this study.

Adolescent↗

Amino acid substitutions alter the tissue distribution of murine interferon-alpha 1.

Novel analogs created by site-directed mutagenesis of murine interferon-alpha 1 (IFN-alpha 1) were used to examine the effect of alterations in structure and biological activity of murine IFN-alpha 1 on tissue distribution in mice. The analogs were biosynthetically labeled with [35S]methionine using a cell-free transcription-translation system and injected intravenously into adult male BALB/c mice. Levels of murine IFN-alpha 1 (dpm/gram wet weight) were highest in the liver, spleen, kidney, and lung, lower in the heart, and quite low in testis, brain, skin, and muscle. The tissue distribution of the analogs differed from that of murine IFN-alpha 1. In general, analogs with reduced antiviral activity showed reduced uptake by the spleen and lung. The amount in the kidney of the analog R33E, which has no detectable antiviral activity in vitro, was substantially higher than that of native IFN, suggesting a greater rate of excretion of this analog. An analog of human IFN-alpha 4, which had increased antiviral activity on murine cells, showed increased uptake in the liver, spleen, and lung. These findings, together with the results of a previous study using autoradiography (Johns et al., 1990, Cancer Res. 50, 4718-4723) indicate that nonspecific uptake by parenchymal cells in the liver, spleen, and lung is unaffected by changes in antiviral activity, while specific, receptor-mediated localization of IFN in regions rich in macrophages is reduced in accordance with the reduction in antiviral activity.

Amino Acids↗

Structure-function study of the region encompassing residues 26-40 of human interferon-alpha 4: identification of residues important for antiviral and antiproliferative activities.

The highly conserved amino acid residues Leu-30 and Arg-33 of human interferon-alpha 4 (IFN-alpha 4) have previously been identified as important for biological activity. In this study, the sequence around Arg-33 was targeted to determine the importance of other residues in this region. A library of analogues containing amino acid substitutions spanning residues 26-37 was generated using site-directed and random mutagenesis. Analogues were expressed in vitro and assayed for antiviral and antiproliferative activity on human cells. No significant separation between the antiviral and antiproliferative activities was observed for any of the analogues tested. Substitutions at positions 26, 27, 31, 32, 34, 35, and 37, did not substantially affect biological activity. However, substitution of Phe-36 with arginine resulted in a greater than 100-fold decrease in biological activity. Thus, together with previous data, the residues in this region identified as most important for biological activity include Leu-30, Arg-33, and Phe-36. Recently published models for the three-dimensional structure of human IFN-alpha and the X-ray crystallographic structure of murine IFN-beta, suggest that the region investigated in this study forms a loop at the surface of the protein. Thus, residues Leu-30, Arg-33, and Phe-36, could be involved in binding to the Type-I IFN receptor, or in interactions with signal-transducing molecules.

Base Sequence↗

Selective production of interferon-alpha subtypes by cultured peripheral blood mononuclear cells and lymphoblastoid cell lines.

The biological significance of the existence of multiple interferon-alpha (IFN-alpha) subtypes is unknown but may represent a finely tuned mechanism whereby different subtypes are produced in response to different stimuli. To investigate the expression of individual IFN-alpha subtypes, polyclonal antipeptide antisera designed to react with all IFN-alpha subtypes, or with a particular subtype, IFN-alpha 2 or IFN-alpha 4, have been produced. In this study we demonstrate the utility of these antisera for the detection, using indirect immunofluorescence staining, of intracellular IFN-alpha produced by human peripheral blood mononuclear cells (PBMC) and lymphoblastoid cells. Secreted IFN-alpha was also investigated by bioassay and a sandwich radioimmunoassay (RIA), using two monoclonal antibodies (mAb) and specific for IFN-alpha 4. The PBMC were shown to produce IFN reactive with all three polyclonal antisera, after stimulation with Sendai virus. The lymphoblastoid cells also produced IFN, including IFN-alpha 2, but IFN-alpha 4 was not detected either intracellularly, by immunofluorescence, or in the medium, by sandwich RIA. The immunofluorescence studies also demonstrate that in the absence of viral stimulation IFN-alpha is found in the cytoplasm of PBMC and lymphoblastoid cells but not secreted in detectable levels. The finding that two lymphoblastoid cell lines do not produce the subtype IFN-alpha 4 raises important questions as to whether other cell lines and cell types produce IFN-alpha subtypes selectively, and whether individual IFN-alpha subtypes have different roles in human physiology and pathology.

Biological Assay↗