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PubMed1972

Oxygen-stable hemolysins of group A streptococci. 8. Leukotoxic and antiphagocytic effects of streptolysins S and O.

Streptolysin S exists in a cell-bound form and as an extracellular complex between a nonspecific carrier (serum, serum albumin, ribonucleic acid [RNA], Triton, Tween) and a hemolytic moiety (probably a peptide) synthesized by streptococci. Although all the forms of streptolysin S, at 100 hemolytic units, killed mouse leukocyte monolayers, the time needed to kill 100% of the cells varied with the different streptolysin S preparations. Whereas 30 min was sufficient for the cell-bound hemolysin to kill all of the cells, 60 and 180 min were required when RNA streptolysin S and serum streptolysin S, respectively, were employed. Addition of 10% mouse serum to RNA streptolysin S or to cell-bound hemolysin delayed the killing of the leukocytes. The delayed killing observed with serum and albumin hemolysins is probably due to competition for the hemolytic moiety between the carrier molecules and target sites (phospholipids) upon the leukocyte membrane. Serum streptolysin S must be constantly incubated with the cells for 90 min for 100% of the cells to undergo cytopathic changes upon subsequent incubation for an additional 90 min. Streptolysin S inhibitor (trypan blue) added to the system after 30 or 60 min of incubation resulted in the killing of 50 and 100% of the leukocytes, respectively, when the cells were further incubated for 120 min. It is suggested that 30 min of incubation was not sufficient for the transfer of enough streptolysin S molecules upon the cell surface to allow killing of all of the cells. Sublethal amounts of streptolysin S, streptolysin O, and saponin suppressed phagocytosis of streptococci by mouse peritoneal macrophages. This effect was abolished by inhibitors of streptolysin S (trypan blue) and of streptolysin O and saponin (cholesterol). With sublethal amounts of streptolysin S, no inhibition of the reduction of nitro blue tetrazolium by nonphagocytosing cells was observed, but these amounts of streptolysin S caused a 50% inhibition of the reduction of nitro blue tetrazolium by phagocytosing leukocytes. It is suggested that some metabolic systems, which are normally enhanced during phagocytosis, have been affected by sublethal doses of streptolysin S. The results indicate that the in vivo production of small amounts of streptolysins S and O by group A streptococci may inhibit phagocytosis and may thus contribute to the invasiveness and pathogenicity of this microorganism.

Animals↗
PubMed1969

Dissociation of hemolytic and lymphocyte-transforming activities of streptolysin S preparations.

The ability of streptolysin S preparations to induce high percentages of transformation in human peripheral blood lymphocytes was confirmed in a series of apparently healthy donors. Transforming activity was not demonstrated in the two media used for streptolysin S production, nor in control preparations in which a strain each of Streptococcus viridans, Staphylococcus aureus (nonhemolytic), and Diplococcus pneumoniae was substituted for the beta hemolytic streptococcal strain used for streptolysin S production. The relation of the hemolytic activity to the lymphocyte transforming activity of streptolysin S preparations was studied by means of inactivation and fractionation experiments. Heating produced a loss in both activities, but more in the hemolytic than in the transforming activity. The transformation obtained with a heated preparation had a high degree of correlation with that obtained with the unheated preparation in a series of normal subjects and patients with various rheumatic diseases, whose lymphocytes were often less responsive to stimulation with streptolysin S preparations (both heated and unheated) than the lymphocytes of the normal subjects studied. Treatment of streptolysin S preparations with chymotrypsin, vegetable lecithin, or trypan blue (the latter in minute amounts) resulted in preparations with no detectable hemolytic activity but with undiminished lymphocyte transforming activity. Chromatographic fractionations on DEAE-Sephadex columns yielded fractions endowed with transforming but not with hemolytic activity, and other fractions endowed with hemolytic but not with transforming activity. The recovery of the hemolytic activity was not complete and quantitation of the recovery of the transforming activity was not attempted. These experiments indicate that the hemolytic and transforming activities of streptolysin S preparations are independent of each other, and specifically that they are the attributes of two different streptococcal products, one of which is streptolysin S. The other is a nonhemolytic streptococcal product present in streptolysin S preparations but previously unrecognized. Some implications of these findings are discussed.

Blood Donors↗
PubMedDate not supplied

Interaction of streptolysin-O with natural and artificial membranes.

1. Kinetic studies on the binding of 125I-streptolysin-O exhibited immediate fixation of activation toxin to natural and artificial membranes. Once fixed to the membrane no release of Streptolysin-O or Streptolysin-O-lipid-complexes has been observed. 2. In contrast to activated toxin (free SH-groups!), oxidized Streptolysin-O was shown to become also fixed to membranes, however, with different binding kinetics. The binding of oxidized amterial was clearly dependent on temperature and time. When the toxin was oxidized twice the amount of labelled material was bound as compared with the hemolytically active Streptolysin-O. This suggests that oxidized Streptolysin-O, too, possesses a "binding site" within the molecule, though free SH-groups were expected to be essential for toxin fixation at the membrane. It has been shown that oxidized (inactive) and reduced (active) Streptolysin-O forms stable "complexes" with liposomes in aqueous which could be separated by chromatography on Sepharose gels. 3. The binding of 125I-toxin to membranes and liposomes was specific since specific antisera against Streptolysin-O inhibited fixation of toxin completely. 4. Hydrolysis of phospholipids and release of lysophosphatides by Streptolysin O esterase (EC 2.1.2.2) has not been observed, thus providing no evidence for an enzymatic concept for membrane damage.

Antigen-Antibody Reactions↗
PubMed2006

Suicide cancer gene therapy using pore-forming toxin, streptolysin O.

We cloned the streptolysin O gene from the Streptococcus pyogenes genome and tested the possibility of using it as an anticancer reagent. Transient transfection of the streptolysin O gene efficiently killed 293T cells after 12 hours of transfection as determined by lactate dehydrogenase release and propidium iodide uptake. No caspase activity was observed and necrosis was prominent during streptolysin O-induced cell death. Biochemical analysis of streptolysin O protein revealed that the deletion of only 5 amino acids from the COOH-terminal region of streptolysin O, which is essential for cholesterol binding activity, abolished its cell-killing activity, whereas the NH2-terminal region was more resilient, i.e., up to 115 amino acids could be deleted without changing its cell-killing activity. We generated a streptolysin O-expressing adenovirus and injected it into human cervical cancer cell-derived tumors grown in a nude mouse model. Twenty-one days postinjection, the average size of tumors in the streptolysin O adenovirus-injected group was 29.3% of that of the control PBS-treated group. Our results show that the genes of pore-forming toxins, like streptolysin O protein, have the potential to establish a novel class of suicide gene therapeutic reagents.

Adenoviridae↗
PubMed1980

Activation of human neutrophil metabolism by streptolysin O.

The effect of streptolysin O on the metabolic activity of human neutrophils was examined. Streptolysin O, within the range of 3 to 75 hemolytic units, stimulated neutrophils to emit light. This chemiluminescence was the result of metabolic activation, as confirmed by oxygen uptake studies and the suppression of chemiluminescence by the metabolic inhibitor, 2-deoxyglucose. Free cholesterol, which prevents streptolysin O from binding to membrane cholesterol, blocked the neutrophil chemiluminescent response to streptolysin O. Extracellular calcium ions were necessary for the streptolysin O-stimulated chemiluminescent response of neutrophils. Some cell viability was lost, as measured by trypan blue uptake and neutrophil lysis within the range of streptolysin O concentration that caused metabolic stimulation. These observations suggest a possible role for streptolysin O as a pathogenic factor in streptococcal infections.

Calcium↗
PubMed1987

Immunological relation between serum antibodies against pneumolysin and against streptolysin O.

The immunological relation between serum antibodies to pneumolysin and to streptolysin O was studied in patients with pneumococcal pneumonia (n = 40), patients with infections due to beta-haemolytic streptococci (n = 35), healthy human controls (n = 60) and in rabbits immunized with pneumolysin. There was no correlation between anti-pneumolysin and anti-streptolysin O titers (r = -0.279). The distribution of anti-pneumolysin titers in patients with high anti-streptolysin O titers did not differ from healthy controls. However, there was a tendency to increased or rising anti-streptolysin O titers in patients with pneumococcal infection. Antibodies obtained during pneumococcal infection might thus give false-positive reactions in the streptolysin O neutralization test. Serum antibodies to streptolysin O do not cross-react with pneumolysin in an ELISA. The pneumolysin ELISA for detection of pneumococcal disease will therefore not be disturbed by false-positive reactions due to antibodies directed against beta-haemolytic streptococci.

Animals↗
PubMedDate not supplied

Studies on the toxic effects of streptolysin 'O': effect on the contractility of isolated and intact mammalian and amphibian heart.

The effect of streptolysin O (a streptococcal exotoxin) on the myocardial contractility of isolated and intact mammalian and amphibian heart has been investigated. Streptolysin O caused marked reduction or complete cessation of myocardial contractility of mammalian and amphibian heart both in vivo and in vitro. The effect of submaximal doses of streptolysin O on isolated atria was reversible after repeated washings and the myocardial depressant effect of streptolysin O on isolated atria was reversible after repeated washings and the myocardial depressant effect of streptolysin O was not antagonised by atropine. These observations would suggest that streptolysin O is cardiotoxic and may be involved in the causation of myocardial failure associated with acute rheumatic fever in man.

Animals↗
PubMed1964

STUDIES ON LYSOSOMES. IV. SOLUBILIZATION OF ENZYMES DURING MITOCHONDRIAL SWELLING AND DISRUPTION OF LYSOSOMES BY STREPTOLYSIN S AND OTHER HEMOLYTIC AGENTS.

Streptolysins S and O from hemolytic streptococci were found to induce mitochondrial swelling and the release of malic dehydrogenase from mitochondria; no other streptococcal products were as active. Mg(++), cyanide, dinitrophenol, bovine serum albumin, and antimycin all inhibited streptolysin-induced mitochondrial swelling; only the latter two agents prevented release of malic dehydrogenase from the particles. The streptolysins also solubilized beta-glucuronidase from the less numerous lysosomes of mitochondrial fractions. Vitamin A induced swelling of mitochondria with release of malic dehydrogenase and, at higher concentrations, release of beta-glucuronidase. In these effects, streptolysin S and vitamin A resembled cysteine and ascorbate, which induced swelling and lysis of mitochondria together with solubilization of enzymes. In contrast, mitochondrial swelling induced by such agents as phosphate, thyroxine, or substrates was not accompanied by release of enzymes. The release of enzymes from particles is suggested as a criterion for distinguishing "lytic" agents from those which induce mitochondrial swelling dependent upon electron transport. It was possible to dissociate effects on mitochondria and lysosomes in these experiments; less streptolysin was necessary to damage lysosomes than mitochondria; the converse was found with vitamin A. Injury to mitochondria resulted from the direct action of these agents, since the lysosomal enzymes released as a consequence of their action were not capable of inducing mitochondrial swelling or release of enzymes under the conditions studied.

Animals↗
PubMed1964

STUDIES ON LYSOSOMES. V. THE EFFECTS OF STREPTOLYSINS AND OTHER HEMOLYTIC AGENTS ON ISOLATED LEUCOCYTE GRANULES.

Granules from rabbit peritoneal leucocytes were prepared in 0.3 M sucrose as an optically homogeneous suspension with the aid of heparin. Lysis of the granules in vitro was followed by measurement of decreases in the apparent absorbance of the suspensions at 520 mmicro and was accompanied by solubilization of beta-glucuronidase from the particles. Streptolysins O and S from hemolytic streptococci lysed the granules at 20 degrees C; the initial rate of lysis by streptolysin O was greater than that by streptolysin S. Cysteine activated, and specific antibody inhibited, streptolysin O; antimycin and bovine serum albumin inhibited streptolysin S. The granules were not lysed by any other streptococcal exotoxins. Lysis was irreversible and depended neither upon oxidative phosphorylation, nor upon intact respiration. The granules were also lysed by lysolecithin, at concentrations from 2 x 10(-6)M to 1 x 10(-4)M; bovine serum albumin and antimycin also inhibited this lytic agent. Such other hemolytic agents and procedures as vitamin A, non-ionic detergents, and ultraviolet irradiation also disrupted leucocyte granules. In susceptibility to lysis and other properties, the granules of white cells resembled erythrocytes. Leucocyte granules differed from mitochondria in that they did not appear to take up or extrude water reversibly; they were unaffected by thyroxine, phosphate, or metabolic substrate. The studies are compatible with the hypotheses that white cell granules are similar to lysosomes isolated from other tissues, and that they share common surface properties with erythrocytes.

Animals↗
PubMed1963

MOTION PICTURE STUDY OF THE TOXIC ACTION OF STREPTOLYSINS ON LEUCOCYTES.

The initial morphologic alteration in rabbit polymorphonuclear leucocytes exposed to streptolysin is rapid and extensive lysis of cytoplasmic granules. The granules appear to rupture directly into the cell sap. Within a few minutes following degranulation, the leucocyte rounds up, filamentous processes appear on the cell membrane, the cytoplasm liquefies, and finally the nuclear lobes swell and fuse. Streptolysin O causes these changes in intact leucocytes when added in concentrations only slightly higher than those required for release of hydrolases from isolated liver lysosomes, and furthermore exerts its action on granulocytes promptly. On the other hand streptolysin S acts on white cells only after a 15 to 30 minute delay, and the levels necessary to disrupt granules in leucocytes are considerably higher than those which act on lysosome suspensions. Exposure of rabbit alveolar macrophages to streptolysin O also results in lysis of granules, soon followed by alterations in the cytoplasm and membrane. The observations are in accord with the hypothesis that streptolysins penetrate the leucocyte membrane and bring about lysis of granules. Autolytic enzymes released from the granules might then be responsible for the subsequent damage seen in various other cell structures.

Animals↗