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PubMed1955

Effect of metabolic factors on the susceptibility of albino mice to experimental tuberculosis.

Mice maintained on various types of diets were found to become more susceptible to tuberculosis when deprived of food for periods of 30 hours shortly after infection. In contrast, the susceptibility of the animals to the disease was unaffected by undernutrition resulting from limitation of food intake to a low but constant daily level. The resistance of mice to tuberculosis appeared to be independent-within wide limits-of the protein content of the diet. It is true that mice fed a diet very low in protein and high in carbohydrate proved highly susceptible, but resistance was normal if part of the carbohydrate was replaced by fat (peanut oil)-without any change in the protein content of the food. Resistance to tuberculosis could be consistently and markedly decreased by adding sodium citrate (or glutarate) to a variety of diets. The survival time following infection was greatly shortened if dinitrophenol or thyroxine were administered per os in amounts sufficient to limit the weight gains of non-infected controls. There was usually a lag period of several days before the infection-enhancing effect of these metabolic stimulants became manifest. The procedures which increased the susceptibility of mice to infection with virulent tubercle bacilli also made it possible to establish in these animals a fatal infection with BCG. There was no constant relation between weight gains of uninfected mice on the various regimens, and the effect of the latter on susceptibility to tuberculosis. These findings appear compatible with, but do not prove, the hypothesis that a decrease in resistance to infection can be brought about by metabolic disturbances which cause either a depletion of the glycogen reserves of the body, or a reduction in the glycolytic activity of inflammatory cells, or an increase in the concentration of certain polycarboxylic acids and ketones in the tissues.

Animals↗
PubMed1956

Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy.

Observations are presented on the behavior of populations of tubercle bacilli in the tissues of mice during the administration of antimicrobial drugs. The behavior of the populations during therapy with any particular drug was different depending upon whether the tubercle bacilli were subsisting in the lung or in the spleen. Moreover, the pattern of microbial behavior was distinctive and predictable for each drug studied. Changes in the size of the populations of tubercle bacilli in the tissues appeared to be a more sensitive reflection of drug influence than microscopic study of the number and character of the tuberculous lesions. Nevertheless, in untreated animals, pulmonary lesions evolved and progressed steadily to a fatal outcome despite the fact that the populations of tubercle bacilli had stabilized at a relatively high census early in the course of therapy. The uniform persistence of tubercle bacilli in the spleen throughout prolonged drug administration was demonstrated with every drug or multiple drug regimens except for pyrazinamide when accompanied by isoniazid. Cultures of the bacilli which survived in the tissues despite antimicrobial therapy were highly susceptible to the drugs employed when tested in vitro. Thus the survival of the tubercle bacilli in the tissues represented microbial persistence rather than drug resistance. When pyrazinamide and isoniazid were administered together, it was not possible to detect the microorganisms in the spleen or lungs of treated animals. A detailed investigation of this apparent abolition of microbial persistence forms the subject of an accompanying report.

Aminosalicylic Acid↗
PubMed1956

The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug.

Populations of tubercle bacilli of human origin exposed in vivo to pyrazinamide and a companion drug, vanished from the tissues of the mouse in so far as could be determined by microscopy, culture, or guinea pig subinoculation. The vanishing did not represent a complete elimination of the tubercle bacilli from all the animals. 90 days after the completion of treatment, tubercle bacilli could be cultured from approximately one-third of the animals examined at that time. This complete disappearance of the tubercle bacilli thus meets the definition of a truly latent infection in that the infection is present but is hidden beyond the limits of diagnostic reach. All but one of the strains of tubercle bacilli which survived in the animals and were detectable in the posttreatment period, were susceptible to pyrazinamide when tested under appropriate conditions in vitro. Only two factors could be identified which were essential for the uniform occurrence of the disappearance of tubercle bacilli: the administration of the pyrazinamide in a high daily dosage for at least eight of a total of 12 weeks of antimicrobial therapy; and the concurrent or prior exposure of the microbial populations to isoniazid or in some cases to other antituberculous drugs. The observations suggest that the ability of pyrazinamide-containing chemotherapies to bring about the disappearance of a tubercle bacillus is closely related to the occurrence of some alteration in the bacillus, essential for maximal pyrazinamide action, in response to environmental influences, including other antituberculous drugs present in the environment.

Animals↗
PubMed1957

Studies on the interaction between phagocytes and tubercle bacilli. III. Some metabolic effects in guinea pigs associated with infection with tubercle bacilli.

In continuing studies concerning the interactions between phagocytes and tubercle bacilli the effect of tuberculous infection on respiration and glucose utilization was investigated in guinea pigs. Peritoneal exudates rich in polymorphonuclear leucocytes, derived from guinea pigs infected with tubercle bacilli, had a significantly higher rate of respiration than the same cells from normal animals. The difference between cells from normal and infected animals was greater when the animals were infected with a virulent strain (Vallée) than when infected with an attenuated one (R1Rv or BCG). By the use of glucose labelled with C(14) at position 1 or 6, or uniformly labelled glucose, it was established that this difference in oxygen uptake between normal and infected cells was probably not caused by a difference in the pathway of glucose utilization. Similarly, the respiration of liver and kidney slices from normal and infected guinea pigs was compared and it was found that liver slices showed differences similar to those shown by leucocytes, but that the kidney slices did not. The possibility has not been ruled out that the difference in rate of respiration of liver slices due to infection might be caused by tuberculous lesions in the livers of infected animals. The mononuclear cells which invade the liver have a higher rate of oxygen uptake than liver cells. The rate of glucose utilization and the total amount of CO(2) produced was also determined in intact guinea pigs. Both functions were found not to differ significantly in normal and infected animals. The rate of production of CO(2) from C(1) and C(6) of glucose was the same in both groups of animals. The ratio of the rate of production of C(14)O(2) from C(1) and C(6) of glucose by the whole animal was found to be about 1.35. It was found to be much higher with polymorphonuclear leucocytes (C(1)/C(6) = 8 in the absence of serum). During the process of phagocytosis this ratio increased from about 25 to about 130 (in the presence of 2 per cent serum) indicating an increase in the direct oxidative pathway of glucose utilization during stimulated cellular activity.

Animals↗
PubMed1953

Effect of infection with M. tuberculosis and of tuberculin shock on the succinic dehydrogenase activity of guinea pig tissues.

The kidney of guinea pigs infected with the H37Rv and BCG strains of M. tuberculosis showed a diminution in succinic dehydrogenase activity when measured by the tetrazolium technique. This effect was also seen in the liver and spleen of animals infected with the BCG strain. Sensitized animals showed similar results when given tuberculin in sublethal doses. The succinic oxidase was also low in the kidneys of animals infected with the H37Rv strain. The depressed enzyme activity of the tissues of infected animals could be restored to normal by addition of normal tissue extract or dialysate. This suggests that the alteration in tissue metabolism observed in tuberculosis may depend upon the loss of some as yet unidentified factor important for succinic dehydrogenase activity.

Animals↗