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Biomedical subjects

E Tuomanen

Publications and source records attributed to E Tuomanen.

At least 73 records · Page 4Linked to original sources
PubMed1991

Differences of pathophysiology in experimental meningitis caused by three strains of Streptococcus pneumoniae.

Differences in cytochemical and pathophysiologic abnormalities in experimental meningitis caused by pneumococcal strains A, B, and C were determined. Strain C produced the most severe abnormalities of cerebrospinal fluid (CSF) concentrations of lactate (P less than .01), protein (P less than .02), and glucose (P less than .01), CSF white blood cell count (P less than .04), cerebral blood flow (P less than .02), and clinical signs (P less than .05). Brain edema occurred only with strains A anc C, with no association with disease severity; intracranial hypertension was also independent of disease severity. Strain B, not C, achieved the highest bacterial titers in the CSF (P less than .005). The widely different abilities of strains of Streptococcus pneumoniae to induce intracranial abnormalities suggest that virulence determinants affect not only evasion of defense during colonization and invasion, as shown in other models, but also determine the course of disease once infection has been established. Differences of cell-wall metabolism among pneumococcal strains may play a role in this latter phase of the development of meningitis.

Animals↗
PubMed1990

Recognition of a bacterial adhesion by an integrin: macrophage CR3 (alpha M beta 2, CD11b/CD18) binds filamentous hemagglutinin of Bordetella pertussis.

During the course of whooping cough, Bordetella pertussis interacts with alveolar macrophages and other leukocytes on the respiratory epithelium. We report here mechanisms by which these bacteria adhere to human macrophages in vitro. Whole bacteria adhere by means of two proteins, filamentous hemagglutinin (FHA) and pertussis toxin, either of which is sufficient to mediate adherence. FHA interacts with two classes of molecules on macrophages, galactose-containing glycoconjugates and the integrin CR3 (alpha M beta 2, CD11b/CD18). The interaction between CR3 and FHA involves recognition of the Arg-Gly-Asp (RGD) sequence at positions 1097-1099 in FHA. This study demonstrates that bacterial adherence can be based on the interaction of a bacterial adhesin RGD sequence with an integrin and that bacterial adhesins can have multiple binding sites characteristic of eukaryotic extracellular matrix proteins.

Amino Acid Sequence↗
PubMed1990

The role of cytokines in the generation of inflammation and tissue damage in experimental gram-positive meningitis.

Cytokines mediate many host responses to bacterial infections. We determined the inflammatory activities of five cytokines in the central nervous system: TNF-alpha, IL-1 alpha, IL-1 beta, macrophage inflammatory protein 1 (MIP-1), and macrophage inflammatory protein 2 (MIP-2). Using a rabbit model of meningeal inflammation, each cytokine (except IL-1 beta) induced enhanced blood brain barrier permeability, leukocytosis in cerebrospinal fluid, and brain edema. Homologous antibodies to each mediator inhibited leukocytosis and brain edema, and moderately decreased blood brain barrier permeability. In rabbits treated with anti-CD-18 antibody to render neutrophils dysfunctional for adhesion, each cytokine studied lost the ability to cause leukocytosis and brain edema. After intracisternal challenge with pneumococci, antibodies to TNF or IL-1 prevented inflammation, while anti-MIP-1 or anti-MIP-2 caused only a 2-h delay in the onset of inflammation. We suggest these cytokines have multiple inflammatory activities in the central nervous system and contribute to tissue damage during pneumococcal meningitis.

Animals↗
PubMed1990

The vir locus affects the response of Bordetella pertussis to antibiotics: phenotypic tolerance and control of autolysis.

Eradication of Bordetella pertussis from the respiratory tract occurs slowly even when bactericidal antibiotics are used. The rate of killing of B. pertussis was found to be proportional to growth rate: virulent, slowly growing strains were killed over days, while rapidly growing strains (either avirulent or virulent modulated by growth conditions to avirulent) were killed over hours. Minimum inhibitory concentrations and binding of antibiotics to membrane targets were equivalent in virulent and avirulent cells, suggesting differences in antibiotic response might reflect differences in activities of the autolytic cascade. This was supported by the finding that cell wall degradation was less than 40% per day in virulent strains and greater than 70% per day in avirulent strains. Penem antibiotics, known to rapidly kill even slowly growing bacteria, demonstrated a more-than-twofold greater rate of killing of slowly growing virulent strains compared with ampicillin or erythromycin. This suggests the potential for improved therapeutic efficacy in vivo. Thus, the vir locus, which determines phase transition in B. pertussis, is apparently the first example of a sensor-transducer system controlling phenotypic tolerance and antibiotic-induced autolytic activity.

Anti-Bacterial Agents↗
PubMed1990

Mechanism of phenotypic tolerance of nongrowing pneumococci to beta-lactam antibiotics.

Within minutes after the onset of deprivation of an essential nutrient, all bacteria develop resistance to lysis by beta-lactam antibiotics, a phenomenon termed phenotypic tolerance. Two phases of this process were identified in pneumococci and the activity of the major autolysin, an N-acetylmuramyl-L-alanine amidase, was studied in each phase. Autolysin was detectable by immunofluorescence in a uniform distribution over the surface of growing pneumococci, but became progressively depleted during amino acid deprivation. Lysis of nongrowing cells by beta-lactam antibiotics could be reconstituted by addition of exogenous autolysin during the first 80 minutes of starvation (Phase I) but not thereafter (Phase II). Similarly, Triton X-100 or deoxycholate lysed nongrowing cells in Phase I but not Phase II. Cell wall isolated from Phase II cells was found to be more resistant to hydrolysis by the autolysin in vitro than that from growing cells. Lysis of growing cells could also be inhibited by incorporation of a pulse of nonhydrolysable cell wall or autolysin deficient cell wall into the growth zone. These results suggest that phenotypic tolerance in nongrowing pneumococci involves rapid loss or disengagement of autolysin molecules from their in situ attack-sites (Phase I) followed by a second slower process that involves a progressive change in the cell wall structure to a form less susceptible to hydrolysis by the autolysin (Phase II).

Amino Acids↗
PubMed1989

Unusual composition of peptidoglycan in Bordetella pertussis.

The composition of the peptidoglycan of Bordetella pertussis and the nature of its turnover products was determined by a new combination of analytical techniques: high performance liquid chromatography of an enzymatic peptidoglycan hydrolysate and fast atom bombardment mass spectrometry and fast atom bombardment collision-activated dissociation tandem mass spectrometry. Sixteen major components of the peptidoglycan were purified, and assignment of complete or partial chemical structures was achieved for nine and seven species, respectively. At this level of resolution, a previously unrecognized heterogeneity of monomeric (five new species; nine total) and dimeric species (five new species; five total) was detected. No species containing diaminopimelyl-diaminopimelic acid cross-links or lysyl-arginine substitutions were found. Previous estimates of total cross-linkage and average chain length were revised downward to 32% and 21 disaccharide residues, respectively. Detection of a chemically novel species, a disaccharide octapeptide monomer, in both the peptidoglycan hydrolysate and culture supernatant fluid, suggests that an N-acetyl-muramyl-L-alanine amidase acts on the intact peptidoglycan of Bordetella and participates in cell wall turnover. Five peptidoglycan turnover products were identified in the supernatant fluid of late logarithmic phase cultures, including the 1,6-anhydro monomeric species known as tracheal cytotoxin. Peptidoglycan turnover was detected at a low rate of approximately 10%/generation, a value sufficient to account for the generation of all tracheal cytotoxin found in culture supernatant fluids.

Bordetella pertussis↗
PubMed1989

Filamentous hemagglutinin of Bordetella pertussis: nucleotide sequence and crucial role in adherence.

Filamentous hemagglutinin is a surface-associated adherence protein of Bordetella pertussis, which is a component of some new acellular pertussis vaccines. The nucleotide sequence of an open reading frame that encompasses the filamentous hemagglutinin structural gene, fhaB, suggests that proteolytic processing is necessary to generate the mature 220-kDa filamentous hemagglutinin product. An Arg-Gly-Asp (RGD) tripeptide is found within filamentous hemagglutinin that may be involved in its adherence properties. An internal in-frame deletion in fhaB, encompassing the RGD region, causes loss of B. pertussis-binding to ciliated eukaryotic cells, confirming a potential role for this protein in host-cell binding and infection.

Amino Acid Sequence↗
PubMed1989

Inhibition of the binding of penicillin to the pneumococcal penicillin-binding proteins (PBPs) by exogenous cell wall peptides.

Incubation of pneumococci with D-alanine-containing peptides naturally occurring in peptidoglycan protected cells against lysis and killing by beta-lactam antibiotics near MIC. Such peptides caused decreased binding of the antibiotic to penicillin-binding proteins (PBPs), primarily PBP 2B. This provides direct evidence in vivo for the hypothesis that beta-lactams act as substrate analogues and identifies PBP 2B as a killing target in pneumococci.

Alanine↗
PubMed1989

Role of autolysins in the activities of imipenem and CGP 31608, a novel penem, against slowly growing bacteria.

The carbapenem imipenem and the penem CGP 31608 demonstrated unusually good bactericidal activity against slowly growing bacteria. In contrast to that of penicillin, the rate of killing was independent of growth rate. In logarithmically growing cells, a decrease in growth rate was paralleled by a decrease in the relative activity of only one of four autolysins measured (membrane-bound endopeptidase), suggesting that autolysis induced by penicillin G may be rate limited by this enzyme. Imipenem, on the other hand, appeared to trigger different autolysins in Escherichia coli, as evidenced by differences in the structure of peptidoglycan after imipenem- versus penicillin-induced autolysis.

Anti-Bacterial Agents↗
PubMed1989

Production of interleukin-1 but not tumor necrosis factor by human monocytes stimulated with pneumococcal cell surface components.

While there is considerable evidence that both interleukin-1 (IL-1) and tumor necrosis factor (TNF) are central mediators of inflammation caused by gram-negative bacteria and endotoxin, the roles of these two mediators in gram-positive infection are unknown. Pneumococcal infections are characterized by an intense inflammatory reaction in infected tissues. Current evidence suggests that the component of the pneumococcus which causes this inflammation in many body sites is the cell wall. We determined the ability of native pneumococcal cell wall, lipoteichoic acid, and cell wall subcomponents to stimulate secretion of IL-1 and TNF from human monocytes. Each pneumococcal cell surface component was found to have a different specific activity for induction of IL-1. Teichoication was an important determinant of this activity: teichoicated species were at least 10,000-fold more potent than endotoxin and 100-fold more potent than teichoic acid-free peptidoglycan. IL-1-inducing activity was greatly reduced by chemical alteration of the teichoic acid. In contrast to endotoxin, cell wall did not induce production of TNF. This dissociation of the production of IL-1 and TNF during the response of the human monocyte to pneumococcal surface components suggests that, in at least some circumstances, the mechanisms for generation of an inflammatory response to infection may be fundamentally different between gram-positive and gram-negative disease.

Cell Wall↗
PubMed1988

Receptor analogs and monoclonal antibodies that inhibit adherence of Bordetella pertussis to human ciliated respiratory epithelial cells.

The adherence of Bordetella pertussis to human respiratory cilia is critical to the pathogenesis of whooping cough. To explore the development of agents that could interrupt adherence, the structure of the receptor on the ciliary surface was investigated. Using an in vitro adherence assay to human ciliated epithelial cells, galactose, lactose, and complex carbohydrates containing lactose eliminated adherence when preincubated with the bacteria. 10(-2) M galactose eluted adherent bacteria from cilia. B. pertussis and its two purified adhesins bound specifically to natural lactose-containing glycolipids in a TLC assay. mAbs to eukaryotic glycoconjugates with specificity for substituted galactose-glucose moieties blocked adherence when preincubated with ciliated cells. The carbohydrates that serve as receptors for B. pertussis on human cilia are galactose-glucose-containing glycolipids. Receptor analogs and anti-receptor antibodies effectively block adherence of B. pertussis to cilia and thus should be considered candidates for therapeutic intervention against disease.

Antibodies, Monoclonal↗
PubMed1988

A sandwich adhesion on Streptococcus pneumoniae attaching to human oropharyngeal epithelial cells in vitro.

Streptococcus pneumoniae attach to human pharyngeal epithelial cells through the specific interaction of bacterial surface adhesins with glycoconjugate receptors. The present study defines the adhesin as a molecule bridging between an anchoring site in the bacterial cell wall and the epithelial cell receptor. The nature of the adhesin was defined in three ways: First, the attachment of whole bacteria was reduced by trypsin, periodate and heat. Second, heat treatment of whole bacteria was shown to release material, which was able to reconstitute the adherence. The heat extract bound to epithelial cells, as shown by fluorescence labelling, and agglutinated latex beads covalently coupled with receptor oligosaccharide. Active material could be extracted by heat from both high and low adhering strains, but could reconstitute only attaching strains. Third, the bacterial component binding the adhesin was localized to protoplasts and cell wall fractions obtained by mechanical or deoxycholate induced lysis of pneumococci. Isolated pneumococcal surface components, which did not inhibit attachment, included peptidoglycan, C polysaccharide, Forssmann antigen, capsular polysaccharide and a phenol extract produced in analogy to streptococcal lipoteichoic acid. The procedure used to extract the adhesin was previously used to prepare the competence factor. The competence deficient mutant RA7- attached poorly compared to the competent R6 parent. The possible relatedness of attachment to competence is discussed.

Adhesins, Bacterial↗
PubMed1988

The contribution of pneumococcal cell wall to the pathogenesis of experimental otitis media.

We studied the contribution of pneumococcal cell wall to the pathogenesis of otitis media in chinchillas after middle ear inoculation of killed, encapsulated type 7F Streptococcus pneumoniae; killed, unencapsulated R6 S. pneumoniae; and isolated R6 pneumococcal cell wall. Ears inoculated with encapsulated and unencapsulated pneumococci had significantly higher concentrations of polymorphonuclear and mononuclear leukocytes and lysozyme in middle ear fluid and developed more epithelial metaplasia and granulation tissue than did saline-inoculated ears. The mean concentration of lysozyme in middle ear fluid was higher in ears inoculated with killed, unencapsulated than encapsulated pneumococci. The middle ear mucoperiosteum of ears inoculated with pneumococcal cell wall showed significantly more polymorphonuclear leukocytes, epithelial metaplasia, subepithelial congestion, and granulation tissue than did control ears. Because nonviable, unencapsulated pneumococci and pneumococcal cell wall caused middle ear inflammation in the chinchilla model of otitis media, it is possible that cell envelope and cell wall components released during bacterial lysis may contribute to chronic otitis media with effusion in humans.

Acute Disease↗
PubMed1988

Microbiological and clinical significance of a new property of defective lysis in clinical strains of pneumococci.

A pneumococcal isolate that caused relapsing meningitis in a patient infected with human immunodeficiency virus (HIV) was found to display an unusual response to penicillin--rapid death but a striking lack of cellular lysis. This lytic defect was also detected in all four pneumococcal isolates from three additional HIV-infected patients and in more than half of the clinical isolates from patients with bacteremia. In a rabbit model of meningitis, the lysis-defective strain remained cryptic, with a delay of 5 h in the onset of leukocytosis in cerebrospinal fluid. A marked burst of leukocytosis was associated with ampicillin-induced lysis of a lysis-sensitive strain but not of a lysis-defective strain. Pneumococcal clinical isolates have different lytic responses to penicillin; defective lysis may adversely affect the course of meningitis, an observation suggesting that autolysins play a role in modulating infectious diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Autolysis-resistant peptidoglycan of anomalous composition in amino-acid-starved Escherichia coli.

Nongrowing Escherichia coli deprived of an essential amino acid continued to produce peptidoglycan at a rate approximately 30% of that of growing cells. The composition of this peptidoglycan was very different from that of growing cells and resembled that of peptidoglycan left undegraded during partial autolysis of the bacteria. Synthesis of this peptidoglycan of anomalous composition began at once upon the removal of the amino acid from the medium. Fifteen minutes of amino acid deprivation was sufficient to virtually completely prevent penicillin-induced autolytic wall degradation in vivo. During this time, although the specific activities of soluble and membrane-bound hydrolytic transglycosylases and endopeptidases remained high, the peptidoglycan produced showed decreased sensitivity to degradation in vitro. After more extensive (2-h) starvation, triggering of autolysis by chaotropic agents was also blocked. Autolysis in growing cells may be selective for peptidoglycan representing the cylindrical portion of the sacculus. It is suggested that at least part of the mechanism of the well-known lysis resistance of nongrowing E. coli is related to the deposition of structurally anomalous and relatively autolysin-resistant peptidoglycan at some strategically located sites on the bacterial surface.

Amino Acids↗