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R J DUBOS

Publications and source records attributed to R J DUBOS.

At least 19 recordsLinked to original sources
PubMed1962

The fecal flora of various strains of mice. Its bearing on their susceptibility to endotoxin.

Adult mice from seven different colonies were studied with regard to (a) the numbers and types of bacteria that could be cultivated from their stools; (b) their resistance to the lethal effect of endotoxins prepared from three strains of Gram-negative bacilli. See PDF for Structure In six of the seven colonies, the stools yielded large numbers of various types of lactobacilli, enterococci, and Gram-negative bacilli. Most animals in these colonies died within 48 hours following injection of endotoxin. The other mouse colony (NCS) has been maintained for the past three years at the Rockefeller Institute under exacting sanitary conditions; it is free of many types of common mouse pathogens. The stool flora of NCS mice yielded very large numbers of viable lactobacilli (10(9) per gm), representing at least three different morphological types. In contrast, it contained only few enterococci and Gram-negative bacilli (less than 10(6) per gm). Moreover, E. coli, Proteus sp., and Pseudomonas sp. could not be recovered from the stools under normal conditions. NCS mice proved resistant to the lethal effect of endotoxins. These characteristics of the NCS colony prevailed whether the animals were housed continuously in individual cages on wire grids, or grouped continuously in large cages with wood shavings as litter. However, the composition of the bacterial flora could be rapidly and profoundly altered by a variety of unrelated disturbances such as sudden changes in environmental temperature, crowding in cages, handling of the animals, administration of antibacterial drugs, etc. The first effect of the change was a marked decrease in the numbers of lactobacilli and commonly an increase in the numbers of Gram-negative bacilli and enterococci. When tested 3 weeks after these disturbances some NCS animals were found to have become susceptible to the lethal effects of endotoxin.

Animals↗
PubMed1962

The effect of diet on the fecal bacterial flora of mice and on their resistance to infection.

A study was made of the effect of certain dietary regimens on the lactobacillus flora in the stools of mice and on their resistance to infection. Semi-synthetic diets with purified casein or wheat gluten as sole source of protein, gave rise to much smaller numbers of viable lactobacilli in the stools than did other diets containing unidentified natural products-as present for example in mixtures of whole wheat and whole milk, or in certain commercial pellets. Furthermore, one of the lactobacillus types with rhizoid morphology disappeared completely from the stools of animals fed the semi-synthetic diet. The change in the lactobacillus flora became apparent within a very few days after the animals had been shifted from the complex to the synthetic diet Moreover, this change was not completely reversible. Whereas the total numbers of lactobacilli increased when the animals were shifted back from the synthetic to the complex diets, the rhizoid lactobacilli which had disappeared completely from the stools reappeared only slowly or not at all. In twelve consecutive experiments the three diets which gave rise to the large numbers of lactobacilli in the stools also conferred on the mice a much higher resistance to experimental infection with Staphylococcus aureus and Klebsiella pneumoniae, than did the semi-synthetic diets. However, direct evidence has not yet been obtained that the two kinds of phenomena were causally related. Following administration of endotoxin there was a rapid and very large increase in the numbers of enterococci and coliform bacilli in mice fed the semi-synthetic casein diet, but not in those fed the pellets. In two preliminary experiments carried out with another colony of mice, not pathogen-free, it was also found that the rhizoid type of lactobacilli disappeared from animals fed the semi-synthetic casein diet while enterococci and coliform bacilli progressively increased in numbers under the same conditions. The dietary effects on the lactobacillus flora, and on resistance to experimental infection, were equally pronounced whether the mice were housed in individual cages on wire grids, or grouped in larger cages with wood shavings as litter. This was true even if the bedding was changed only once weekly and became therefore grossly soiled.

Animals↗
PubMed1961

The effect of bacterial endotoxins on the water intake and body weight of mice.

Injection of endotoxin of Gram-negative bacilli into NCS mice caused an immediate reduction or interruption of water intake by these animals, with a resultant loss of body weight. Endotoxins prepared by three different techniques from four different cultures of Gram-negative bacilli yielded products having approximately the same activity in inhibiting water intake. The minimum effective dose was 0.1 microg. or less. With all toxin preparations tested, the duration of the effect was directly related to the dose injected. The heat-killed cells of Esch. coli proved approximately as effective as the endotoxins prepared from Gram-negative bacilli. In contrast, heat-killed cells of Mycobacterium tuberculosis (BCG) were much less active, and heat-killed cells of Staphylococcus aureus were essentially inactive. Mice previously treated with endotoxin exhibited a marked degree of tolerance to the inhibition of water intake caused in normal animals by a subsequent treatment with the same material. Tolerance could also be induced by vaccination with heat-killed Gram-negative bacilli. Tolerance overlapped from one bacterial species to another but was more pronounced toward the endotoxin prepared from the bacterial culture with which the animal was vaccinated. The duration of the inhibitory effect of endotoxin on water intake was much shorter with mice fed a complete diet than with mice fed a deficient diet (corn). It took approximately the same dose of endotoxin (0.1 microg.) to inhibit water intake, reduce the influx of polymorphonuclear leucocytes, and enhance staphylococcal infection.

Animals↗
PubMed1961

The susceptibility of mice to bacterial endotoxins.

Albino mice (Rockefeller NCS strain) raised and maintained free of ordinary bacterial pathogens, as well as of intestinal Escherichia coli and of Proteus bacilli, were found to be highly resistant to the lethal effect of bacterial endotoxins. When newborn mice of this NCS colony were nursed by foster mothers from another colony raised under ordinary conditions (SS colony from which the NCS colony was derived), they acquired the intestinal flora of the latter animals and became susceptible to the lethal effects of endotoxins. NCS adult mice could be rendered susceptible to the lethal effect of endotoxins by vaccination with heat killed Gram-negative bacilli. The susceptibility thus induced exhibited a certain degree of specificity for the bacterial strain used in vaccination. Although untreated NCS mice were resistant to the lethal effect of endotoxins, they proved exquisitively susceptible to the infection-enhancing effect of these materials. For example, 1 microg. or less of endotoxin was found sufficient to help establish a rapidly fatal septicemia with Staphylococcus aureus. Small amounts of endotoxin (1 microg. or less), administered alone, caused a marked but transient loss of weight. Vaccination with heat-killed Gram-negative bacilli or with killed BCG increased the resistance of NCS mice to the infection-enhancing effect of small amounts of endotoxin. This protective effect exhibited a certain degree of specificity for the bacterial strain from which the toxin used in the infection-enhancing test was derived. These various findings can be explained by assuming that the pathological effects of endotoxins involve at least two unrelated mechanisms; (a) a primary toxicity illustrated in this study by the loss of weight and enhancement of infection resulting from the injection of small doses of toxin; (b) an immunological reaction with lethal consequences which became manifest only in animals sensitized to the endotoxin by prior exposure to Gram-negative bacilli.

Animals↗
PubMed1960

The effect of the intestinal flora on the growth rate of mice, and on their susceptibility to experimental infections.

Mice delivered by Caesarian section were used to develop a new mouse colony which has been maintained in an environment protected from contact with common mouse pathogens, but not in the germ-free state. These mice, designated as NCS, were compared with animals of the same sex and age coming from the parent colony maintained under ordinary conditions. The NCS mice grew more rapidly than ordinary mice on complete diets; moreover, they continued to gain weight-although at a slower rate-when fed deficient diets which caused ordinary mice to stop growing, or to lose weight. The NCS mice proved much more susceptible than ordinary mice to certain experimental bacterial infections. In contrast, they were much more resistant than ordinary mice to the lethal effect of large doses of endotoxins. However, they responded to injection of minute amounts of these endotoxins by a marked increase in susceptibility to staphylococcal infection. Bacteriological studies revealed striking qualitative differences between the intestinal flora of NCS and ordinary mice. When NCS mice were contaminated-either by contact or by feeding-with a strain of Escherichia coli recovered from the intestine of ordinary mice, they acquired the characteristics of the latter animals with regard to weight gain on various diets, and to response to bacterial pathogens and endotoxins. NCS mice have been found well suited to the study of several nutritional, bacteriological, and immunological problems and it appears that their production on a large scale will not present unsurmountable difficulties.

Animals↗
PubMed1959

Effect of dietary proteins and amino acids on the susceptibility of mice to bacterial infections.

Young mice were maintained for periods of 1 to 6 weeks on experimental diets containing all known growth factors, but differing in their protein and amino acid contents. All diets were supplemented with L-cystine. The effect of the nutritional regimen on infection was tested by inoculating the animals with either one of four pathogens (Mycobacterium tuberculosis var. bovis, Mycobacterium fortuitum, Staphylococcus aureus, Klebsiella pneumoniae type C), and by observing the survival time. The infective dose was administered by either one of three routes: intravenous, intraperitoneal, or air-borne (aerosol). In some experiments, the animals were maintained in groups of five throughout the tests. In other experiments they were housed in individual cages. This difference in housing did not affect the results in a detectable manner. Mice fed diets containing 5 or 8 per cent casein as sole source of amino acid (except for cystine supplementation) proved more susceptible to the experimental diseases than did mice fed diets containing 15 or 20 per cent of the same protein. Susceptibility to infection developed when wheat gluten, or soybean alpha-protein, was substituted for casein-even in high concentrations (15 or 20 per cent). In one experiment, mice were fed a diet containing as sole source of amino acids a mixture of soybean and rice flour, so designed as to provide a protein concentration of 15 per cent, with an amino acid pattern similar to that of casein. These animals gained weight at the same rate as those fed a diet containing 15 per cent casein and they exhibited a satisfactory level of resistance to bacterial infection. The infection-enhancing effect of low casein concentration (5 and 8 per cent) could be corrected by supplementing the diet with the proper mixture of amino acids. This could be done using either synthetic or natural amino acids. In contrast, susceptibility to infection developed when low casein diets were supplemented with unbalanced mixtures of amino acids. The infection-enhancing effect of gluten diets could not be corrected by supplementing the latter with lysine even though this supplementation markedly improved weight gains in uninfected animals. It appears in conclusion that the relative proportion of the various amino acids in the diet is as important a factor as their total amount in conditioning resistance to bacterial infections. This effect of nutrition on resistance can be detected irrespective of the route of infection: intravenous, intraperitoneal, or air-borne. Moreover, the effect has been observed with two strains of mice differing markedly in their natural resistance to bacterial infection.

Amino Acids↗
PubMed1959

Effect of nutrition on the resistance of mice to endotoxin and on the bactericidal power of their tissues.

Mice on inadequate nutritional regimens were found to be more susceptible to various bacterial diseases than mice fed a complete diet containing 15 to 20 per cent casein. The tests of susceptibility included: (a) infections with virulent bacteria; (b) injection of large doses of avirulent coagulase-negative staphylococci; and (c) lethal effects of bacterial endotoxins. The infection-enhancing effect of nutritional deficiencies could be rendered even more striking by administering the infective inoculum simultaneously with a sublethal dose of endotoxin. Despite their great susceptibility to infection, malnourished animals retained much of their ability to eliminate bacteria from the blood, liver, spleen, kidneys, and lungs, at least during the early phases of the infectious processes. This was true even when the animals had received endotoxin simultaneously with the infective dose. The results suggest that under the conditions of the present study, the nutritional state influenced the outcome of infection not primarily by affecting the fate of the pathogens in vivo, but rather by modifying the ability of the host to resist their toxic effects.

Animals↗
PubMed1959

Studies on fractions of methanol extracts of tubercle bacilli. I. Fractions which increase resistance to infection.

Fractionation procedures yielding partially purified vaccine preparations from a 60 degrees C. methanol extract of tubercle bacilli have been described. Some of the preparations have the characteristics of lipopolysaccharides. Certain ones have been found capable of increasing resistance to experimental tuberculosis in albino mice of the Rockefeller Swiss strain. The levels of resistance elicited by these preparations are equivalent to those following vaccination with BCG (Phipps) in this strain of mice as reported by other authors. The admixture of two of the crude fractions in amounts as small as 0.05 mg. each per dose per mouse affords an even greater increase in resistance. Neither of these substances alone in larger doses can approach this degree of efficacy in mouse protection experiments. The protective activity appears to involve the stimulation of two supplementary mechanisms, one providing a peak resistance between 1 and 3 weeks post vaccination but falling off to a lower level thereafter, the other not responding fully until approximately 6 weeks but continuing undiminished through a 12 week post-vaccination period. The first of these peaks corresponds to an increase in resistance against staphylococci as well as tubercle bacilli. The possibility that the term "broad specificity," rather than "non-specificity," might best describe this phenomenon permits the implication of classical immune mechanisms.

Animals↗
PubMed1958

Effect of dietary proteins and amino acids on the susceptibility of mice to bacterial infections.

Groups of young albino mice were fed continuously four different types of diets and were compared with regard to (1) rate of weight gain; (2) resistance to experimental bacterial infections. The protein content of the four diets was as follows: (a) pellets: a minimum of 21 per cent "crude" protein (according to the manufacturer); (b) diet 20 C: 20 per cent casein; (c) diet 8 C: 8 per cent casein; (d) diet 8 C + AA: 8 per cent casein supplemented with 12 per cent of a mixture of essential amino acids. All diets provided an adequate supply of minerals and vitamins. They were administered ad lib. Three strains of pathogens virulent for mice were used for the infection tests, namely: Staphylococcus aureus, Mycobacterium fortuitum, and Mycobacterium tuberculosis bovis. The bacteria were injected by the intravenous route. The experimental regimens were begun at different times before infection, and were continued until death of the animal, or until termination of the experiment. It was found that mice on the 8 C diet exhibited much greater susceptibility to infection than did mice on the 20 C diet; mice receiving pellets were intermediate between these two groups. The infection-enhancing effect of the 8 C diet could be entirely corrected by amino acid supplementation (diet 8 C + AA). Indeed, mice fed diet 8 C + AA proved the most resistant to infection. The fact that animals fed pellets (which contain a minimum of 21 per cent protein) consistently died faster following infection than did animals fed diets 20 C or 8 C + AA suggests that qualitative characteristics of the protein in the regimen are as important as the quantity of protein fed in determining susceptibility to infection. The differences in susceptibility exhibited by the mice on the four experimental diets were the same whatever the species of bacterial pathogen used for the infection test, the size of the infective dose, and the duration of the disease. There was no apparent relation between the effects of the diets on the weight curves of the animals, and on resistance to infection. Mice on diet 8 C (which were most susceptible) gained weight as rapidly as those on 20 C and more rapidly than those fed 8 C + AA (which were most resistant). All the tests reported in the present paper were carried out with young mice, which were placed on experimental diets within 1 to 2 weeks after weaning. Preliminary experiments suggest that the relation between dietary factors and susceptibility to infection was more difficult to bring out in older animals. There was evidence also that this relation was most apparent during the first weeks that the animals were fed the experimental diets, and became less striking after several weeks.

Amino Acids↗