Crossreactions between Legionella and Campylobacter spp.
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Antibodies, Bacterial↗
Biomedical subjects
R J Fallon
Publications and source records attributed to R J Fallon.
Sporadic cases of Legionnaires' disease.
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Disease Reservoirs↗
The effect of staurosporine, a protein kinase inhibitor, on asialoglycoprotein receptor endocytosis.
Receptor-mediated endocytosis via coated pits is modulated by the activity of protein kinases and protein phosphorylation. We examined the effects of the potent protein kinase inhibitor staurosporine (SSP) on endocytosis of the asialoglycoprotein (ASGP) receptor in HepG2 cells. Staurosporine caused a rapid (< 2 min) inhibition of ligand internalization from the cell surface. In contrast the rate of receptor exocytosis from intracellular compartments to the cell surface was not altered (t1/2 = 8 min). This resulted in increased ASGP receptors at the plasma membrane (140% of control) while the total number of receptors per cell was unchanged. Receptor up-regulation was half-maximal at 30 nM SSP. At this concentration staurosporine also inhibited the internalization of iodinated transferrin by HepG2 cells and SK Hep-1 cells, another human hepatoma-derived cell line. Staurosporine was without effect on the non-receptor-mediated uptake of Lucifer yellow by pinocytosis. We investigated the possible involvement of protein kinase C in the inhibitory effects of staurosporine on receptor endocytosis. The active protein kinase C inhibitor H7 did not inhibit ASGP receptor internalization. Furthermore depletion of cellular protein kinase C by overnight incubation with 1 microM phorbol myristate acetate did not abrogate the SSP effect. Together these data suggest that the mechanism of SSP action is independent of the inhibition of protein kinase C. In conclusion staurosporine is a potent and rapid inhibitor of receptor trafficking which is specific for receptor internalization from the plasma membrane.
Alkaloids↗
Hospital-acquired meningococcaemia.
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Bacteremia↗
The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide.
The serpin-enzyme complex (SEC) receptor mediates catabolism of alpha 1-antitrypsin (alpha 1-AT)-elastase complexes and increases in synthesis of alpha 1-AT in cell culture. The SEC receptor recognizes a pentapeptide domain on alpha 1-AT-elastase complexes (alpha 1-AT 370-374), and the same domain in several other serpins, amyloid-beta peptide, substance P, and other tachykinins. Thus, it has also been implicated in the biological properties of these ligands, including the neurotoxic effect of amyloid-beta peptide. In this study, we examined the possibility that the SEC receptor mediates the previously described neutrophil chemotactic activity of alpha 1-AT-elastase complexes, and whether the other ligands for the SEC receptor have neutrophil chemotactic activity. The results show that 125I-peptide 105Y (based on alpha 1-AT 359-374) binds specifically and saturably to human neutrophils, and the characteristics of this binding are almost identical to that of monocytes and hepatoma-derived hepatocytes. Peptide 105Y and amyloid-beta peptide mediate chemotaxis for neutrophils with maximal stimulation at 1-10 nM. Mutant or deleted forms of peptide 105Y, which do not bind to the SEC receptor, have no effect. The neutrophil chemotactic effect of alpha 1-AT-elastase complexes is blocked by antiserum to peptide 105Y and by antiserum to the SEC receptor, but not by control antiserum. Preincubation of neutrophils with peptide 105Y or substance P completely blocks the chemotactic activity of amyloid-beta peptide, but not that of FMLP. These results, therefore, indicate that the SEC receptor can be modulated by homologous desensitization and raise the possibility that pharmacological manipulation of this receptor will modify the local tissue response to inflammation/injury and the neuropathologic reaction of Alzheimer's disease.
Alzheimer Disease↗
Amyloid-beta peptide, substance P, and bombesin bind to the serpin-enzyme complex receptor.
During the formation of an inhibitory complex with neutrophil elastase, alpha 1 antitrypsin (alpha 1 AT) undergoes a structural rearrangement and the resulting alpha 1 AT-elastase complex becomes endowed with chemoattractant activities, mediates an increase in synthesis of alpha 1 AT, and is rapidly cleared from the circulation. In previous studies we have provided evidence that these biological activities involve the recognition of a conformation-specific domain in the alpha 1 AT molecule by a cell surface receptor on human hepatoma HepG2 cells and human monocytes. The receptor has been termed the serpin-enzyme complex (SEC) receptor because it also recognizes complex of serpins antithrombin III, alpha 1 anti-chymotrypsin, and C1 inhibitor with their cognate enzymes. Because a pentapeptide domain of alpha 1 AT (amino acids 370-374, Phe-Val-Phe-Leu-Met) is sufficient for binding to the SEC receptor and the sequence of this domain is remarkably similar to those of substance P, several other tachykinins, bombesin, and the amyloid-beta peptide, we have examined the possibility that these other ligands bind to the SEC receptor. The results indicate that substance P, several other tachykinins, and bombesin compete for binding to, and cross-linking of, the SEC receptor. The SEC receptor is distinct from the substance P receptor by several criteria. There is no substance P receptor mRNA in HepG2 cells; the SEC receptor is present in much higher density on receptor-bearing cells and binds its ligands at lower affinity than the substance P receptor; the SEC receptor is much less restricted in the specificity with which it recognizes ligand; ligands for the SEC receptor including peptide 105Y (based on alpha 1 AT sequence 359-374), alpha 1 AT-protease complexes, and bombesin do not compete for binding of substance P to a stable transfected cell line expressing the substance P receptor. Finally, we show here that the amyloid-beta peptide competes for binding to the SEC receptor but does not bind to the substance P receptor, therein raising the possibility that the SEC receptor is involved in certain biological activities, including the recently described neurotrophic and neurotoxic effects ascribed to the amyloid-beta peptide.
Amino Acid Sequence↗
Haemophilus influenzae type b invasive disease.
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Child, Preschool↗
The SEC receptor recognizes a pentapeptide neodomain of alpha 1-antitrypsin-protease complexes.
Formation of the covalently stabilized alpha 1-antitrypsin (alpha 1-AT)-neutrophil elastase complex, the archetype of serpin-enzyme complexes, results in a structurally rearranged alpha 1-AT molecule that possesses chemo-attractant activities, mediates an increase in synthesis of alpha 1-AT by mononuclear phagocytes and hepatocytes, and is more rapidly cleared from the circulation than is the native alpha 1-AT molecule. We have recently identified an abundant, high affinity cell surface receptor on human hepatoma HepG2 cells and human monocytes that binds alpha 1-AT-elastase complexes, mediates endocytosis and lysosomal degradation of alpha 1-AT-elastase complexes, and induces an increase in synthesis of alpha 1-AT. We have referred to this receptor as the serpin-enzyme complex, or SEC, receptor because it also recognizes complexes of serpins antithrombin III, alpha 1-antichymotrypsin, and C1 inhibitor with their cognate enzymes. In the current study, we show that a pentapeptide domain in the carboxyl terminal fragment of alpha 1-AT (amino acids 370-374, FVFLM) is sufficient for binding to the SEC receptor. A synthetic analog of this pentapeptide (peptide 105C, FVYLI) blocks binding and internalization of alpha 1-AT-125I-trypsin complexes by HepG2 cells. 125I-Peptide 105C binds specifically and saturably to HepG2 cells, and its binding is blocked by alpha 1-AT-trypsin or alpha 1-AT-elastase complexes. Alterations of this sequence introduced into synthetic peptides (mutations, deletions, or scrambling) demonstrate that binding of the pentapeptide domain is sequence-specific. Comparisons with the sequences of other serpins in the corresponding region indicate that this pentapeptide neodomain is highly conserved.
Amino Acid Sequence↗
A pool of intracellular phosphorylated asialoglycoprotein receptors which is not involved in endocytosis.
One proposed function of the asialoglycoprotein receptor in hepatocytes is to mediate the endocytosis of galactose and N-acetylgalactosamine-exposing glycoproteins. Recently we defined a pool of intracellular H1 subunits of the asialoglycoprotein receptor (ASGPR) in the human hepatoma cell line HepG2 which appeared not to be involved in endocytosis (Stoorvogel, W., Geuze, H. J., Griffith, J. M., Schwartz, A. L., and Strous, G. J. (1989) J. Cell Biol. 108, 2137-2148). In addition, a pool of stably phosphorylated intracellular ASGPR has been detected (Fallon, R. J., and Schwartz, A. L. (1988) J. Biol. Chem. 263, 13159-13166). In the current study we integrate these findings and provide evidence for the existence of two types of intracellular nonexchangeable compartments containing ASGPR. A transiently phosphorylated pool of ASGPR shuttles between the plasma membrane and endosomes, via a pathway identical to that of the transferrin receptor. The second pool comprises 20% of the total intracellular ASGPR, is stably phosphorylated at a serine residue, and is located in intracellular compartments devoid of recycling transferrin receptor. We refer to this ASGPR pool as the "silent pool." We furthermore show that the two receptor pools are confined to compartments exhibiting different buoyant densities on sucrose density gradients. ASGPR in the "silent pool" is fully glycosylated, suggesting a post-Golgi sorting mechanism for trafficking to this compartment. Possible functions of the "silent" ASGPR pool are discussed.
Asialoglycoprotein Receptor↗
Benign meningococcaemia: a rash diagnosis?
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Child↗
Hepatic protein tyrosine phosphatases in the rat.
Regulation of cell growth and metabolism by protein tyrosine phosphorylation involves dephosphorylation via the action of protein tyrosine phosphatases (PTPases). We have characterized the membrane PTPases in rat liver, monitoring their activity by measuring the dephosphorylation of P-Tyr-reduced, carboxyamidomethylated and maleylated lysozyme (P-Tyr-RCML) and P-Tyr-myelin basic protein (P-Tyr-MBP). Separation of membrane PTPases by poly (L-lysine) chromatography yielded three peaks of PTPase, termed I, II and III. PTPases I and II were most active with P-Tyr-RCML, whereas PTPase III showed greater activity with P-Tyr-MBP than with P-Tyr-RCML (ratio of activities 4:1). Separation of membrane proteins by gel-filtration chromatography yielded two peaks of activity. Based on substrate specificity, sensitivity to inhibitors and requirement for thiol-containing compounds, the activity peak with an Mr of approximately 400,000 corresponded to PTPase III, whereas that with an Mr of approx. 40,000 contained PTPases I and II. All three PTPases dephosphorylated epidermal growth factor receptors and insulin receptors, but only PTPases I and II were active with P-Tyr-asialoglycoprotein receptors. Although none of the above characteristics distinguished between PTPases I and II, only PTPase I reacted in a Western immunoblotting procedure with anti-peptide antibodies directed towards human placental PTPase. We conclude that the membrane fraction from rat liver contains at least three distinct PTPases.
Animals↗
Proximity of the home to a cooling tower and risk of non-outbreak Legionnaires' disease.
OBJECTIVE: To study the source of non-outbreak legionnaires' disease, particularly the role of cooling towers, by comparing the locations of patients' homes in relation to the location of cooling towers. DESIGN: Retrospective, descriptive study of a case series of patients with legionnaires' disease ill between 1978 and 1986 and, for comparison, a case series of patients with lung cancer. A prospectively developed register and interview based survey provided data on the location of cooling towers. SETTING: The city of Glasgow. PATIENTS: 134 patients aged 14-84 with legionnaires' disease during 1978-86 and 10,159 patients with lung cancer during the same period. MAIN OUTCOME MEASURES: The locations of patients' homes and cooling towers as defined by postcodes, which provided map grid references accurate to 10 m; numbers of expected and observed cases of legionnaires' disease in census enumeration districts; and distance of enumeration districts from the nearest cooling tower as defined by five distance categories. RESULTS: Most cooling towers were in or near the city centre or close to the River Clyde, as were the places of residence of patients with community acquired, non-travel, non-outbreak legionnaires' disease (n = 107). There was an inverse association between the distance of residence from any cooling tower and the risk of infection, the population living within 0.5 km of any tower having a relative risk of infection over three times that of people living more than 1 km away. There was no such association with respect to travel related legionnaires' disease, and for lung cancer the association was weak (relative risk less than or equal to 1.2 in any distance group). CONCLUSION: In Glasgow cooling towers have been a source of infection in two outbreaks of legionnaires' disease and, apparently, a source of non-outbreak infection also. Better maintenance of cooling towers should help prevent non-outbreak cases. This method of inquiry should be applied elsewhere to study the source of this and other environmentally acquired disease.
Adolescent↗
The effects of buscopan compositum on calf nutritional diarrhoea.
Nutritional diarrhoea was induced in male Friesian calves by the addition of sucrose to their milk replacer diet in two experiments. In each study the calves were paired on the basis of the severity of the diarrhoea and each of a pair of calves was assigned at random to receive a course of six intramuscular injections (5 ml/50 kg body weight) of either a placebo or Buscopan compositum (morning and evening) over a period of 3 days. In an initial study, which involved 10 pairs of calves, daily faecal and urine output were collected separately for each calf on the day prior to the start of treatment and on each day of the 3 treatment days. The daily output of fresh faeces were reduced as a result of treatment with Buscopan compositum and the overall reduction for the complete 3 day period was 18.7%. This was also reflected in a reduced output of faecal water (18.4%) during the same period. The digestibility of the dry matter component of the diet was significantly increased by 5.8%. In a second experiment, which involved 24 pairs of calves, faecal samples were collected daily, commencing before initiation of treatment, for determination of faecal dry matter content. The pattern of change in the faecal dry matter content during the course of the study differed clearly for the two treatments. Faecal dry matter increased from its lowest level (11.7%), immediately prior to first treatment, to its maximum (21.8%) on the second day of treatment in the Buscopan compositum-treated calves.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Low concentrations of primaquine inhibit degradation but not receptor-mediated endocytosis of asialoorosomucoid by HepG2 cells.
Asialoorosomucoid (ASOR) is internalized and degraded by HepG2 cells after binding to the asialoglycoprotein (ASGP) receptor, internalization through the coated pit/coated vesicle pathway, and trafficking to lysosomes. Primaquine, an 8-aminoquinoline antimalarial compound, inhibits ASOR degradation at concentrations greater than 0.2 mM by neutralizing intracellular acid compartments. This leads to alterations in surface receptor number, receptor-ligand dissociation, and receptor recycling. We have investigated the effects of primaquine on 125I-ASOR uptake and degradation as a function of primaquine concentration and duration of exposure. Concentrations below those required for neutralization of acidic compartments block 125I-ASOR degradation in HepG2 cells and lead to intracellular ligand accumulation. This effect is maximal at 80 microM primaquine. The intracellular 125I-ASOR is undegraded, dissociated from the ASGP receptor, and contained within vesicular compartments distinct from lysosomes, plasma membrane, or endosomes. In addition, the effect of 80 microM primaquine on 125I-ASOR degradation is very slowly reversible (greater than 6 h), in contrast to primaquine's rapidly reversible effect on receptor recycling and ligand uptake (10 min). Furthermore, the effect is ligand-specific. 125I-asialofetuin, another ASGP receptor ligand, is internalized and degraded in lysosomes at normal rates in HepG2 cells exposed to 80 microM primaquine. These findings indicate that primaquine has multiple effects on the uptake and degradation of ligand occurring in the endosome-lysosome pathway. These effects of primaquine differ in their concentration-dependence, site of action, reversibility, and ligand selectivity.
Asialoglycoprotein Receptor↗
Seasonal variation of Legionnaires' disease in Scotland.
A summer and autumn peak in incidence is a characteristic epidemiological feature of Legionnaires' disease, a fact which may help in diagnosis. Previous reports from Scotland have reported a winter peak. This study examined the seasonal variation in Legionnaires' disease in Scotland in each year and by category of diagnosis. A characteristic summer/autumn peak was seen for travel-related infection. For non-travel infection, there was an autumnal peak between 1978 and 1982 but an early winter peak between 1983 and 1986. Overall, the pattern could be described as a summer/autumn plateau reaching a peak in early winter. This pattern, seen in men and women, was clearest in the Greater Glasgow area. Nosocomial cases were clustered in the months of October, November and December. In non-travel cases the classical seasonal pattern was not observed and clinicians cannot rely upon this epidemiological feature for diagnosis. However, the relative infrequency of the disease between January and May was a consistent and potentially useful feature. Most reports on seasonal variation are based on aggregated data on travel and non-travel cases. The present observations question the hypotheses developed to explain the seasonal pattern and call for further studies.
Cross Infection↗
Variation in time and space of non-outbreak Legionnaires' disease in Scotland.
The main aim of this study was to measure and explain geographic variations in the incidence of Legionnaires' disease in Scotland, particularly to help understand the source of non-outbreak infection. Between 1978 and 1986 the overall mean annual incidence rate was 7.9 per million (range 3.1-20.2), and for non-outbreak, non-travel cases it was 5.6. There were geographical variations by health board, by city and within cities, e.g. the mean annual incidence rate per million for non-travel, non-outbreak disease was 1.2 in Tayside Health Board, 3.7 in Lanarkshire, 5.6 in Lothian and 14.4 in Greater Glasgow. In Greater Glasgow Health Board non-travel cases lived in and around the city centre and in some postcode sectors there, the mean annual incidence rate exceeded 100. Travel-related cases lived in peripheral areas. These variations could not be explained by differences in access to and use of diagnostic services, surveillance, or host susceptibility (as reflected by socioeconomic status and frequency of other respiratory disease). The explanation probably lay in environmental factors, though differences in agent virulence were not excluded. The two main conclusions are, that non-outbreak cases were not truly sporadic, and that the space-time variations in incidence support the hypothesis that cooling towers were an important source of infection for non-travel, non-outbreak cases. If so such infection is potentially preventable.
Adolescent↗
Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor.
Alpha 1-Antitrypsin (alpha 1-AT) is similar to other members of the serine protease inhibitor (serpin) supergene family in that it undergoes structural rearrangement during the formation of a covalently stabilized inhibitory complex with its cognate enzyme, neutrophil elastase. We have recently demonstrated an abundant, high-affinity cell surface receptor on human hepatoma cells and human mononuclear phagocytes which recognizes a conformation-specific domain of the alpha 1-AT-elastase complex as well as of other serpin-enzyme complexes (Perlmutter, D. H., Glover, G. I., Rivetna, M., Schasteen, C. S., and Fallon, R. J. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3753-3757). Binding to this serpin-enzyme complex (SEC) receptor activates a signal transduction pathway for increased expression of the alpha 1-AT gene and may be responsible for clearance of serpin-enzyme complexes. In this study, we show that there is time-dependent and saturable internalization of alpha 1-AT-elastase and alpha 1-AT-trypsin complexes in human hepatoma HepG2 cells. Internalization is mediated by the SEC receptor as defined by inhibition by synthetic peptides corresponding to residues 359-374 of alpha 1-AT. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of intracellular radioactivity demonstrated that intact 75- and 66-kDa alpha 1-AT-trypsin complexes were internalized. Kinetic analysis of internalization at 37 degrees C showed that a single cohort of 125I-alpha 1-AT-trypsin complexes, prebound to cells at 4 degrees C, disappeared from the cell surface and accumulated intracellularly within 5-15 min at 37 degrees C. The intracellular concentration of radiolabeled complexes then decreased rapidly coincident with appearance of acid-soluble degradation products in the extracellular culture fluid. Intracellular degradation was inhibited by internalization at 18 degrees C or by internalization at 37 degrees C in the presence of weak bases ammonium chloride, primaquine, and chloroquine, indicating that degradation is lysosomal. These results indicate that in addition to its role in signal transduction the SEC receptor participates in internalization and delivery of alpha 1-AT-protease complexes to lysosome for degradation.
Carcinoma, Squamous Cell↗