Biomedical subjects
Publications and source records attributed to L J Berry.
Corticosteroid induction of mouse hepatic phosphoenolpyruvate carboxykinase was inhibited by prior injection of poly I:C. Mice challenged with a lethal dose of endotoxin 4 h after administration of poly I: C could not be protected by a concurrent injection of hydrocortisone.
Nonmotile mutants of Vibrio cholerae isolated from Ogawa, Inaba, and El Tor strains were less virulent than parent wild types when administered to adult mice intraperitoneally. The cells were suspended in 5% hog gastric mucin. Antitoxic immunity did not protect mice against this type of challenge, but a ribosomally derived vaccine did. Intraperitoneal injection of 10 50% lethal doses of enterotoxin (based on intravenous doses) was without toxic manifestations as were 10(10) heat-killed vibrios similarly administered, regardless of strain. Virulent organisms killed with formalin or ultraviolet irradiation were significantly lethal at a dose of 10(10) cells. Mice made tolerant to endotoxin were protected from death caused by an injection of 3 X 10(10) boiled cells, but they did not survive an injection of formalin-killed cells. It is believed that the cause of death in this animal model of cholera is dependent, at least in part, on a toxic heat-labile moiety closely associated with the vibrios.
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The ability of motile strains of the Ogawa and Inaba serotypes of classical Vibrio cholerae and of the El Tor biotypes to kill suckling mice after oral challenge with 10-8 colony-forming units (representing at least 100 to 1,000 minimal lethal doses) was compared to that of nonmotile derivatives of the same strains. Loss of motility, in each case, resulted in a marked reduction in virulence. The mortality (at 36 h) caused by 10 of the 13 nonmotile strains was 32% or less. whereas the motile wild-type strains resulted in nearly 100% deaths. The reduced virulence of the nonmotile strains was associated with reduced capacity to adsorb to the surface of segments of mouse intestine. The mutants were tested for alterations in enterotoxin production and surface properties. The results suggest that motility may contribute to virulence by increasing the chance for association of the vibrios with the intestinal mucosa.
The susceptibility of suckling mice to oral infection with several different Vibrio cholerae was determined. Mice up to 10 days of age were uniformly susceptible to oral infection with 10(8) colony-forming units of virulent organisms. Age-dependent resistance occurred thereafter to a maximum at about 15 days of age. The efficacy of selected vaccines was compared by oral challenge of 8-day-old, passively immunized CFW mice. An Ogawa-derived ribosomal antigen was found to be superior to a commercial whole-cell vaccine or to purified cholera enterotoxin. The ribosomal antigen was 50- to 100-fold more protective than the other vaccines on a weight basis against otherwise lethal challenge with Ogawa, Inaba, or El Tor Ogawa serotypes.
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This study was undertaken to characterize the nature of carbohydrate loss due to endotoxin poisoning in mice and to elucidate mechanisms responsible for the changes. Female ICR mice, fasted overnight, were injected intraperitoneally with a mean lethal dose of endotoxin extracted from Salmonella typhimurium strain SR-11. Liver glycogen levels, alanine-U-(14)C and pyruvate-2-(14)C incorporation into blood glucose and liver glycogen, glucose-U-(14)C incorporation into liver glycogen, and liver glycogen synthase activities were measured at intervals after treatment. Liver glycogen in fasted mice given endotoxin was diminished significantly as early as 1 h after treatment. Liver glycogen synthase was significantly decreased in poisoned mice at 17 h. The use of actinomycin D showed that the induction of this enzyme due to fasting or hydrocortisone, or both, was inhibited by endotoxin. The incorporation of the (14)C-label from alanine-U-(14)C, pyruvate-2-(14)C, or glucose-U-(14)C into blood glucose and liver glycogen was substantially impaired in endotoxemic animals at 12 h. Decreases in incorporation occurred as early as 4 h after treatment. The progressive increase in glycogen synthase activity observed in fasted controls was not seen in endotoxin-poisoned mice. The administration of a glucose or pyruvate load to endotoxin-treated mice did not restore gluconeogenesis, glycogen synthesis, or liver glycogen synthase activity to normal levels. The in vivo activation of glycogen synthase by glucose was significantly reduced in endotoxemic animals. These changes indicate reduced carbohydrate synthesis as a probable cause for rapid sugar loss during endotoxemia in mice.
An apparent inhibition of induction of mouse hepatic tryptophan oxygenase by endotoxin has been reported previously, as evidenced by low catalytic activity. This could be due either to decreased tryptophan oxygenase levels or to inactivation of existing enzyme molecules. To resolve this question, the enzyme was quantitated immunologically in control and endotoxin-poisoned mice. Tryptophan oxygenase was purified and used as an antigen to prepare antienzyme antibodies. The antiserum was shown to be monospecific by immuno-electrophoresis. Addition of the antiserum to high-speed supernatant fluids of liver homogenates of control or endotoxin-poisoned mice resulted in precipitation of the enzyme. Radial immunodiffusion assays revealed that there was less enzyme in livers of mice that received 1 mean lethal dose of endotoxin. It was concluded that endotoxin interfered with the synthetic process that results in enhanced levels of tryptophan oxygenase.
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The effect of endotoxin on the activation of phosphoenolpyruvate carboxykinase by tryptophan was studied.
Phosphoenolpyruvate carboxykinase (PEPCK) was precipitated from supernatant fluids of whole mouse liver homogenates by specific antiserum but not by normal rabbit immunoglobulin G. The slopes of inactivation curves were similar for supernatant fluids of control and poisoned mice. It was demonstrated by radial immunodiffusion that PEPCK activity assayed enzymatically was proportional to the diameter of precipitin rings in all cases, except when the enzyme was activated by tryptophan, a process not requiring new enzyme synthesis. Hence, the assay can be used to distinguish between enhanced catalytic activity due to increased enzyme levels or as the result of activation of existing enzyme molecules. Immunological quantitation of PEPCK showed that endotoxin inhibits the induction of the enzyme due to fasting between 4 and 8 hr after administration of the bacterial poison. This result is almost identical to that seen when livers of mice poisoned with actinomycin D were assayed for PEPCK by the radial immunodiffusion technique.
Hepatic fructose-1, 6-diphosphatase and glucose-6-phosphatase were significantly decreased in fasted mice 17 hr after the intraperitioneal injection of a median lethal dose of Salmonella typhimurium endotoxin. Liver glycogen levels were essentially depleted at 17 hr.
An interferon-inducing RNA, SK&F 42319, obtained from a lysate of phage-infected Escherichia coli, protected mice against Vibrio cholerae infection. This nonspecific protection was not attributable to endotoxin contamination.
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An injection of a small dose (1 to 50 mug) of synthetic polyriboinosinic acid complexed with polyribocytidylic acid (poly I:poly C) inhibited the induction of tryptophan oxygenase by cortisone acetate; it induced tyrosine amino transferase, and it accelerated the loss of liver glycogen reserves. It also resulted in first a suppression followed by an activation of the reticuloendothelial system as judged by the rates of carbon clearance from blood. All of these responses are elicited by comparable doses of endotoxin. Pretreatment of mice with poly I:poly C did not, or only marginally, increased their nonspecific resistance to infection with several bacterial pathogens, and it failed to result in the development of tolerance to endotoxin, effects known to be produced by endotoxin when given under similar conditions.